Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is known as a major receptor for oxidized low-density lipoproteins (oxLDL) and plays a significant role in the genesis of atherosclerosis. Recent research has shown its involvement in cancer, ischemic stroke, and diabetes. LOX-1 is a C-type lectin receptor and is involved in the activation of immune cells and inflammatory processes. It may further interact with pathogens, suggesting a role in infections or the host’s response. Summary: This review compiles the current knowledge of potential implications of LOX-1 in inflammatory processes and in host-pathogen interactions with a particular emphasis on its regulatory role in immune responses. Also discussed are genomic and structural variations found in LOX-1 homologs across different species as well as potential involvements of LOX-1 in inflammatory processes from the angle of different cell types and organ-specific interactions. Key Messages: The results presented reveal both similar and different structures in human and murine LOX-1 and provide clues as to the possible origins of different modes of interaction. These descriptions raise concerns about the suitability, particularly of mouse models, that are often used in the analysis of its functionality in humans. Further research should also aim to better understand the mostly unknown binding and interaction mechanisms between LOX-1 and different pathogens. This pursuit will not only enhance our understanding of LOX-1 involvement in inflammatory processes but also identify potential targets for immunomodulatory approaches.

Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells [1]. The triggering of the host immune response depends, at least in part, on the interaction between conserved microbial molecules known as pathogen-associated molecular patterns (PAMPs) and various PRRs [2]. Depending on the specific PAMP-PRR interactions, different signaling pathways can activate a cellular immune response to fight the invading pathogen.

Four distinct families of PRRs are particularly important in the immune response and have been extensively characterized within various cellular compartments: (i) the family of the Toll-like receptors expressed on the cell surface and within endosomes; (ii) the family of C-type lectin-like receptors (CTLRs) primarily residing in the transmembrane cellular region; (iii) the nucleotide-binding oligomerization domain (NOD)-like receptors; and (iv) the retinoic acid-inducible gene-I-like receptors (RLR) predominantly located in the cytoplasmic regions [3‒5]. Besides PAMPs, several PRRs are capable of detecting damage-associated molecular patterns (DAMPS), which are commonly released by damaged cells, for example, during tissue destruction that can occur during proinflammatory immune responses in the host [5].

The different PRR families possess the ability to recognize various ligands, enabling them to detect pathogens or cell damage. NOD-like receptors mainly recognize bacterial cell wall components, microbial toxins, fungal PAMPs, viral RNA, or complete pathogens. Conversely, RIG-like receptors primarily bind to single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) [6].

Toll-like receptors predominantly bind to bacterial lipopeptides, lipopolysaccharides, dsRNA, ssRNAs, and single-stranded DNA (ssDNA) [6]. The CTLRs exhibit a vast array of ligand specificity, although much of the underlying mechanisms still remain unknown. Notably, they frequently interact with various carbohydrate structures. For instance, Dectin-1 specifically binds to β-1,3-glucans, whereas Dectin-2’s interactions involve high-mannose structures such as Man9GlcNAc2. However, some CTLRs can recognize a broader spectrum of ligands, which encompasses proteins and lipids [7]. The function and signaling pathways of many CTLRs are already known, as shown by Drouin et al. [8]. In the past couple of years, another member of the CTLR family has been gaining increasing attention: the low-density lipoprotein receptor-1 (LOX-1). While this receptor is primarily known for its involvement in the genesis of atherosclerosis, several reports from the past few years suggest that it could also function as a PRR, involved in the detection of microbial ligands and in the orchestration of antimicrobial innate immune responses during infections. Therefore, this review aimed to summarize the existing literature on the role of LOX-1 in infectious diseases.

The CTLR superfamily is a prominent class of PRRs that recognize and bind a wide variety of endogenous and exogenous ligands. They also play an important role in immunity and the maintenance of homeostasis [8, 9].

CTLRs form a family of transmembrane PRRs expressed primarily by myeloid cells. Not only do they recognize pathogen moieties for host defense but also modified self-antigens such as damage-associated molecular patterns (DAMPs) released from necrotic and apoptotic cells [8]. CTLRs play an important role in maintaining tissue homeostasis and contributing to antimicrobial host defense. Furthermore, they are involved in various cellular functions such as cell-cell adhesion, lipid scavenging, orchestration of immunity against tumors, virus-infected self-cells, allergies, and the induction of autoimmune reactions [9].

Primarily expressed in myeloid immune cells, CTLRs encompass transmembrane receptors containing at least one highly conserved C-type lectin domain (CTLD). In some cases, they are cleaved to adopt a soluble form that participates in cellular processes [8, 10]. The distinctive folding of the CTLD is characterized by disulfide linkage between several conserved cysteine residues.

Despite the high structural similarity of different CTLDs, they can recognize a wide range of unrelated ligands. This versatility often allows them to engage with different classes of ligands, an attribute known as multivalence [10]. Most of the C-type lectins bind to ligands containing D-mannose, D-glucose, and related sugars, as well as D-galactose and its derivatives. These interactions are facilitated by the CTLD [8, 11]. These ligands are categorized as Man-type and Gal-type ligands [11]. These sugars are distributed on the surface of various pathogens as well as on dead cells.

This is particularly well described for fungi. For example, α-mannose on the surface of Aspergillus fumigatus serves as a ligand for Mincle [12]. The domain contains a Ca2+-dependent and conserved motif known as carbohydrate recognition domain, which operates in a Ca2+-dependent manner to facilitate binding [8]. On the basis of this motif, Drickamer proposed a conceptual framework in 1988 suggesting the organization of the Ca2+-dependent lectins which exhibit structural similarity to asialoglycoprotein receptors into a unified category termed C-type lectins [13, 14].

The receptors lacking this Ca2+-dependent motif are called CTLRs [8]. For now, however, the term CTLRs is used both for the superordinate group of C-type lectins and for the non-Ca2+-dependent subgroup. Within this review, the term CTLR is used to refer to the superordinate group of C-type lectins. In addition, C-type lectins are nowadays classified into 17 different groups based on their structure and function. These are described in detail elsewhere [14].

Through the wide range of binding ligands, CTLRs can mediate diverse downstream responses. These include, for example, steering adaptive immune responses, regulating homeostasis, facilitating the uptake of microorganisms, and mediating cell-cell adhesion [15]. Some of the CTLRs, such as Dectin-1 or Dectin-2, are known particularly for their ability to bind to microorganisms [16]. Functioning as PRRs, these receptors play a major role in microbial infections and immune responses [16]. Other CTLRs, such as DNGR-1, are primarily involved in binding self-ligands, such as damaged or dead cells, or are able to bind both self and microbial ligands, as seen with receptors such as Mincle and DC-SIGN [16].

Dectin-1 and -2 Cluster

The most prominent CTLRs belong to the Dectin-1 and Dectin-2 clusters [17]. Dectin-1 is one of the most thoroughly studied CTLRs, and many of its characteristics are well defined. In contrast, the other receptors within the Dectin-1 cluster have received less scrutiny in terms of their signaling profiles. Some of these receptors possess a hemi-immunoreceptor tyrosine-based activation motif (hemITAM) which activates the SYK-CARD9 pathway, while others have an immunoreceptor tyrosine-based inhibitory motif (ITIM) that inhibits intracellular signaling [15, 18].

While the Dectin-2 cluster belongs to the Group II CTL family and the Dectin-1 cluster to Group V CTL family, both consist of a single CTLD, stalk region, transmembrane region, and an intracellular signaling domain [15, 19]. Dectin-2 cluster members associate with the ITAM-bearing adapter protein, Fc receptor γ-chain (FcRγ), thereby initiating activation of the Syk-CARD9 pathway. Notably, the distinction in signaling arises from the employed signaling motifs used. The Dectin-2 cluster predominantly employs ITAM motifs, except for DCIR, which acts as an inhibitory receptor due to its cytoplasmic ITIM. In contrast, members of the Dectin-1 cluster utilize either ITIM or hemi-ITAM motifs for signaling [18, 19].

The Dectin-2 family contains the CTLRs BDCA-2, DCAR, DCIR, Dectin-2, CLECSF8, and Mincle [17, 19]. While they are all similar in structure, they lack a homologous signaling motif [17, 19]. Serving as multifunctional receptors, they play roles in both immunity and homeostasis and function as PRRs [17, 19]. The receptors are involved in recognizing a variety of pathogens, primarily viruses and fungi [17, 19]. Furthermore, the Dectin-2 family has been implicated in different autoimmune disorders and type I diabetes [19]. A more detailed examination of this topic can be found in other reviews [17, 19].

The Dectin-1 cluster comprises type II transmembrane receptors, including MICL, CLEC1, CLEC2, CLEC9A, CLEC12B, Dectin-1, and LOX-1 [10, 18, 20]. They all consist of a single CTLD and do not appear to require calcium for ligand binding. Members of this cluster are also implicated in diverse diseases and physiological functions [18]. A more detailed explanation of the Dectin-1 cluster is given in other reviews [10, 18]. While Dectin-1 is widely studied, knowledge is still lacking regarding signaling and function of the other family members. The Dectin-1 cluster members are mainly associated with functions in immunity and infection responses.

Overall, the LOX-1 stands out due to being mainly known for its involvement in atherosclerosis and cardiovascular diseases. Despite this limited knowledge about LOX-1 signaling during infection, a rising number of publications indicate its involvement in the immune response in fungal, bacterial, and viral infections [18].

Low-Density Lipoprotein Receptor-1

LOX-1, also known as OLR1, CLEC8A, and SCARE1 [10, 21], is best known for its role as receptor of oxidatively modified low-density lipoprotein (oxLDL), which is a form of low-density lipoprotein after oxidative modification [22]. LDL circulates in the blood and transports cholesterol to peripheral tissues or to the liver for degradation. Elevated LDL levels lead to foam cell formation of macrophages, marking an early stage of atherosclerosis [23].

LOX-1 is the main scavenger receptor of oxLDL, responsible for its recognition, binding, and internalization. Its critical role was first described in 1997 by Sawamura et al. [24]. However, there are also other scavenger receptors, like class A scavenger receptor SRAI/II and class B scavenger receptor CD36, who are able to bind, recognize, and internalize oxLDL [25]. Further information on oxLDL recognition is discussed elsewhere [25].

LOX-1 has further been identified as an important receptor in the pathogenesis of atherosclerosis, facilitating the uptake of oxLDL into endothelial cells within the arterial wall, which triggers inflammatory responses and oxidative stress. Oxidative stress further converts native LDL to oxLDL, which in turn upregulates the LOX-1 activation. For oxLDL uptake, human LOX-1 is clathrin-independent but dynamin-2-dependent and controlled by the DDL tripeptide motif [26]. Moreover, LOX-1 is involved in different immune-relevant pathways, including apoptosis, arginase II activation (contributing to endothelial dysfunction), cytokine production, and the upregulation of the MAPK/NF-κB pathways. It is further involved in ROS production, which induces mitochondrial damage and upregulates the activity of the NLRP3 inflammasome [27, 28]. LOX-1 expression has also been shown to be upregulated in many typical risk factors for atherosclerosis, such as hypertension, diabetes, and dyslipidemia [27, 29]. Furthermore, an upregulation of LOX-1 can be detected after a coronary artery occlusion and reperfusion [27]. Figure 1 provides an overview of the signaling pathways and their effects on cardiovascular diseases (Fig. 1). A more detailed overview about LOX-1 in atherosclerosis is given elsewhere [27].

Fig. 1.

Schematic overview of LOX-1-regulated pathways in cardiovascular diseases. Stated are agents upregulating LOX-1 (top of the figure) as well as factors being upregulated (green arrows) or downregulated (red arrows) upon LOX-1 activation and the resulting physiological effects (in bold). Created with BioRender.com.

Fig. 1.

Schematic overview of LOX-1-regulated pathways in cardiovascular diseases. Stated are agents upregulating LOX-1 (top of the figure) as well as factors being upregulated (green arrows) or downregulated (red arrows) upon LOX-1 activation and the resulting physiological effects (in bold). Created with BioRender.com.

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In addition, LOX-1 is capable of triggering antigen cross-presentation and facilitating protective antitumor immunity [30]. Given its expression on immune-relevant cells and its potent ability to regulate inflammatory responses, LOX-1 expression could also play a major role in infectious diseases and infection response. This review discusses several results that support this hypothesis.

Structure of LOX-1

LOX-1 is a homodimeric type II transmembrane protein, with the dimers linked via intermolecular disulfide bonds (Fig. 2). It comprises four different domains, as shown in Figures 2 and 3. The intracellular N-terminal part consists of a short cytoplasmic region (34 residues; Fig. 3), followed by a transmembrane region, an extracellular coiled-coil region, and a neck domain (80 residues; Fig. 3), which is finally linked to a conserved C-type lectin-like domain (CTLD, 130 residues) [24, 32‒34].

Fig. 2.

Schematic illustration of the LOX-1 receptor. In the cytoplasmatic membrane, LOX-1 exists as disulfide-linked homodimer. It consists of a CTL domain (CTLD), a neck domain (neck), a transmembrane domain (TM), and a cytoplasmic domain (CT) with an amino acid tail. The disulfide bridge stabilizing the human LOX-1 dimer is marked in orange. Created with BioRender.com.

Fig. 2.

Schematic illustration of the LOX-1 receptor. In the cytoplasmatic membrane, LOX-1 exists as disulfide-linked homodimer. It consists of a CTL domain (CTLD), a neck domain (neck), a transmembrane domain (TM), and a cytoplasmic domain (CT) with an amino acid tail. The disulfide bridge stabilizing the human LOX-1 dimer is marked in orange. Created with BioRender.com.

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Fig. 3.

Schematic representation of the human OLR1 gene and the LOX-1 primary protein structure. a Shown is the gene structure with the promotor region of OLR1 and the CAAT and TATA boxes as well as the position and length of the exons (based on data from Ensembl.org version 108 [31]). b Protein structure of LOX-1 showing the different domains of LOX-1 (colors) and the cysteine 140 location.

Fig. 3.

Schematic representation of the human OLR1 gene and the LOX-1 primary protein structure. a Shown is the gene structure with the promotor region of OLR1 and the CAAT and TATA boxes as well as the position and length of the exons (based on data from Ensembl.org version 108 [31]). b Protein structure of LOX-1 showing the different domains of LOX-1 (colors) and the cysteine 140 location.

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LOX-1 is encoded by the 19-kilobases-long gene OLR1. The presence of TATA and CAAT boxes in the promoter region of OLR1 suggests that LOX-1 is not a house-keeping gene but rather an inducible regulated gene [35].

The primary structure of LOX-1 exhibits high genetic homology across different species (Fig. 4a). However, rodents are an exception. A comparison of the LOX-1 genome in different species (Fig. 4a) reveals that the rodent gene shares less than 50% similarity with human LOX-1, while human LOX-1 displays a similarity of over 98% with great apes. This low similarity to rodents is in contrast to many other PRR families, showing a much higher similarity between human and rodent genes. For comparison, NOD-like receptors exhibit higher homology with similarity values exceeding 77% (Fig. 4b). There is also another peculiarity in rodent LOX-1, namely, a repeat of part of the coiled-coil domain (nucleotides 421–699) that is not present in other mammals (Fig. 5). This segment comprises two additional exons that appear to be repetitions of part of the third exon. Whether this additional segment has functional influences on the affinity or specificity of ligands, their binding, the tertiary structure of the receptor, or the induction of intracellular signaling pathways of LOX-1 has not been reported thus far. On the protein level, human and murine LOX-1 show an identity of only 60.7% over an overlap of 183 residues using Expasy alignment [36]. An AlphaFold-generated model of dimeric LOX-1 (Fig. 6) illustrates the elongated coiled-coil region of the rodent protein [37]. While the N-terminal cytoplasmic tail is predicted to be unstructured, the transmembrane domain, the coiled-coil helices, and the C-terminal CTLD are modeled with high confidence. The highly conserved CTL domain displays relatively low similarity values between genomic human and mouse sequences (74%, Fig. 4a). These analyses were conducted using data from Ensembl org version 108 [31].

Fig. 4.

Comparative analysis of PRR-coding gene homologs across different species. a Analysis of the LOX-1 gene homologs and the CTLD-region showing the similarity (in percentage) to the human LOX-1 sequence (based on coding sequence analysis on Ensembl.org version 108 [31]). b Comparison of homologs from different PRR families (NLR, TLR, RLR, CTLR) between human and mouse. Shown are the similarity values for each of the receptor-coding genes (based on data from Ensembl.org version 108 [31]).

Fig. 4.

Comparative analysis of PRR-coding gene homologs across different species. a Analysis of the LOX-1 gene homologs and the CTLD-region showing the similarity (in percentage) to the human LOX-1 sequence (based on coding sequence analysis on Ensembl.org version 108 [31]). b Comparison of homologs from different PRR families (NLR, TLR, RLR, CTLR) between human and mouse. Shown are the similarity values for each of the receptor-coding genes (based on data from Ensembl.org version 108 [31]).

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Fig. 5.

Phylogenetic tree for OLR1 across different species. The left side shows the maximum likelihood phylogenetic tree generated by the Gene Orthology/Paralogy prediction method pipeline within Ensembl.org version 108 [31]. The right side of the figure shows the genetic organization of OLR1 and the alignments between phylogenetic groups. It depicts a transcribed structure in the middle of the OLR1 gene, which is only present in mice, rats, and partially in Cricetidae, representing a genomic difference to the gene structure found in humans and other species.

Fig. 5.

Phylogenetic tree for OLR1 across different species. The left side shows the maximum likelihood phylogenetic tree generated by the Gene Orthology/Paralogy prediction method pipeline within Ensembl.org version 108 [31]. The right side of the figure shows the genetic organization of OLR1 and the alignments between phylogenetic groups. It depicts a transcribed structure in the middle of the OLR1 gene, which is only present in mice, rats, and partially in Cricetidae, representing a genomic difference to the gene structure found in humans and other species.

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Fig. 6.

Model of human and murine LOX-1 protein. The left side shows a model of human and murine LOX-1 dimer, generated with Alphafold [37]. The alignment of the human and mouse LOX-1 protein sequence is depicted on the right side. The DDL motif is marked in purple.

Fig. 6.

Model of human and murine LOX-1 protein. The left side shows a model of human and murine LOX-1 dimer, generated with Alphafold [37]. The alignment of the human and mouse LOX-1 protein sequence is depicted on the right side. The DDL motif is marked in purple.

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The disulfide bond formed at Cys140 in humans and apes mediates the covalent dimerization of the receptor [33, 34]. The dimerization is functionally relevant and human LOX-1 was found to be homodimerized in the cell membrane of a Chinese hamster ovary cell model [38]. It was further reported that the dimerization is necessary for the activation of MAP kinases [39]. The human LOX-1 protein is structured as a homodimer in a heart-shaped form. A central hydrophobic tunnel extends through the middle of the protein. Next to the tunnel at each opening is an electrostatically neutral patch of 12 charged residues containing acid-base pairs. The tunnel is proposed to be part of the recognition of different LOX-1 ligands. Because of its structure, it may recognize lipophilic parts of the oxLDL “core aldehydes,” which are ApoB100 oxidation fragments that are still attached to oxLDL.

Other proposed structures, possibly able to be ligands for the tunnel, are peptides like the bacterial peptidoglycan [32]. The CTLD seems to function as another ligand-binding site, that is known to bind pathogens in other CTLRs [40, 41]. These two binding sites could hint toward a potential ability to bind pathogens and a potential role in infections. However, due to the described difference between human and murine CTLDs, functional differences are possible. The folding structure of LOX-1 is stabilized by three conserved intrachain disulfide bonds. Each monomer consists of two antiparallel β-sheets, flanked by two α-helices, formed by the neck region [32, 34]. The neck region is also responsible for building the homodimeric structure, exhibiting a high similarity to the heavy chain of myosin [34, 41]. The two α-helices establish a coiled coil wrapping around each other similar to the myosin tail region [32, 34]. In addition, six basic amino acids are located across the apolar top of the homodimer [32]. In contrast, the cytoplasmic domain contains a DDL tripeptide motif that could mediate LOX-1 endocytosis (Fig. 7) [45]. This sets LOX-1 apart from other members of the Dectin clusters, as these mostly possess ITAM, ITIM, or hemITAM motifs, as illustrated in Figure 7 [15, 18, 19, 45]. Aside from the fact that DDL is essential for the uptake of oxLDL, the signaling pathway and exact functionality have not yet been elucidated. However, it should be noted that the DDL motif is not found across species. While humans, rabbits, and pigs have the DDL motif, in rats and mice, for example, only one DD is found at this position (Fig. 6). This could have an impact on the signaling of LOX-1, but it is as of yet unclear how [45]. Rodents, especially mice, are often used for LOX-1 research, but due to the structural differences, it should be further analyzed as to whether there are functional differences between human and rodent LOX-1 and if rodents even are a suitable animal model in this context.

Fig. 7.

Cytoplasmic domains of selected C-type lectins of the Dectin-1 and Dectin-2 clusters. The CTLRs show different cytoplasmic signaling motifs. The main ones are ITAM, ITIM, and hemITAM. The signaling motif of LOX-1, on the other hand, is not yet known. The C-type lectins marked with * do only bind ligands in a dimeric form, while for (*), a dimeric as well as a monomeric form represent active C-type lectins and are therefore able to bind ligands in both forms. Created with BioRender.com. The figure is based on [18, 19], and the dimerization information is based on [16, 42‒44].

Fig. 7.

Cytoplasmic domains of selected C-type lectins of the Dectin-1 and Dectin-2 clusters. The CTLRs show different cytoplasmic signaling motifs. The main ones are ITAM, ITIM, and hemITAM. The signaling motif of LOX-1, on the other hand, is not yet known. The C-type lectins marked with * do only bind ligands in a dimeric form, while for (*), a dimeric as well as a monomeric form represent active C-type lectins and are therefore able to bind ligands in both forms. Created with BioRender.com. The figure is based on [18, 19], and the dimerization information is based on [16, 42‒44].

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Splice Variants

The OLR1 gene is composed of six exons and five introns (Fig. 3) [31]. Exon 1 encodes the 5′-untranslated region and a portion of the cytoplasmic domain. Exon 2 includes the remaining part of the cytoplasmic domain and the transmembrane domain, while exon 3 encodes the NECK domain. Exons 4–6 encode the CTLD and 3′-untranslated region. Three different splice variants can be formed by alternative splicing of these six exons. Transcript variant 1 encompasses the entire OLR1 gene with all 6 exons. Transcript variant 2, also referred to as OLR1D4, is the shortest splice variant and lacks exon 4, thus missing the ligand binding and recognition domains (Fig. 8). Transcript variant 3, known as LOXIN, lacks exon 5 and contains a premature stop codon, leading to a premature termination of translation, resulting in LOXIN missing two-thirds of the CTLD (Fig. 8). This exerts an inhibitory effect (Fig. 8). It dimerizes with LOX-1 and thereby prevents the binding of oxLDL due to a defective binding domain. This diminishes the LOX-1 functionality and protects cells from oxLDL-mediated apoptosis [46]. In addition, there are seven different single nucleotide polymorphisms (SNPs) located in intron 4, 5, exon 5, and the 3′UTR [46, 47]. These SNPs can result in the generation of two different haplotypes: the “risk” (CTGGTT) and the “non-risk” (GCAAGC) type. The risk type is associated with a higher probability of developing myocardial infarction. Individuals with the non-risk type tend to exhibit increased LOXIN expression, contributing to a postulated negative correlation between LOXIN and cardiovascular pathologies. It is further assumed that these splice variants could also have an influence on tumorigenesis and atherosclerosis [46]. An influence on the course of infections or the interaction with infectious agents is not yet known but is possible. However, a distinction between mice and humans is also observed here. Mice produce two different splice variants: D2D5OLR1, which lacks exons 2–5, and D3D5OLR1, which lacks exons 3–5. Furthermore, the binding sites of SRSF1 and SRSF2 overlap only in humans and in certain monkey species, but not in other vertebrates [46]. This emphasizes the need to investigate potential differences in functionality between human and murine LOX-1.

Fig. 8.

Schematic representation of human LOX-1 splice variants LOXIN, sLOX-1, and OLR1D4 and their interactions with LOX-1. Created with BioRender.com, modified from [39].

Fig. 8.

Schematic representation of human LOX-1 splice variants LOXIN, sLOX-1, and OLR1D4 and their interactions with LOX-1. Created with BioRender.com, modified from [39].

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Transcription Factors

Due to limited knowledge about LOX-1 signaling, the involved transcription factors are not yet fully understood. A predictive analysis of the regulatory regions (1,000 bp upstream and downstream of the OLR1 gene) via Motifmap [48, 49] suggests binding sites for several potential transcription factors, including SOX10, IRF8, LEF1, MAFB, FRA1, AP-1, GR, and AP-3 (see Table 1).

Table 1.

Predicted transcription factors (TFs) for OLR1 with their names and the distance to the OLR1 origin

TF nameDistance, bpRegion
SOX10 (SRY-BOX Transcription Factor 10) −940 Upstream 
IRF8 (Interferon Regulatory Factor 8) −533 Upstream 
LEF1 (Lymphoid Enhancer Binding factor 1) −519, −216, 773 Upstream, downstream 
MAFB (MAF BZIP Transcription Factor B) −53 Upstream 
FRA1 (Fos-Related Antigen 1) Downstream 
AP-1 (Activating Protein-1) Downstream 
GR (Glucocorticoid Receptor) 882 Downstream 
AP-3 (Activating Protein-3) 949 Downstream 
TF nameDistance, bpRegion
SOX10 (SRY-BOX Transcription Factor 10) −940 Upstream 
IRF8 (Interferon Regulatory Factor 8) −533 Upstream 
LEF1 (Lymphoid Enhancer Binding factor 1) −519, −216, 773 Upstream, downstream 
MAFB (MAF BZIP Transcription Factor B) −53 Upstream 
FRA1 (Fos-Related Antigen 1) Downstream 
AP-1 (Activating Protein-1) Downstream 
GR (Glucocorticoid Receptor) 882 Downstream 
AP-3 (Activating Protein-3) 949 Downstream 

The analysis was conducted with Motifmap [48, 49] using 1,000 bp upstream and downstream sequence of OLR1, with 0 conservation scores, a false discovery rate of 0.5, and the motif scores NLOD = 0.65 and Z-Score = 1.

Furthermore, several transcription factors are already well described in the literature (Table 1). OxLDL, being the most prominent ligand, regulates LOX-1 through the Oct-1 motif, located 1,556 nucleotides upstream of LOX-1 [50]. However, NF-κB and AP-1 are oxLDL-responsive transcription factors capable of binding the promotor of LOX-1, which correlate with the simulation data in Table 1. The regulatory actions of Oct-1 are described as early events, whereas those of NFκB and AP-1 are downstream events. The NFκB motif at 2,158 nt upstream induces LOX-1 expression after stimulation with angiotensin II. On the other hand, the AP-1 motif located 62 nucleotides upstream activates LOX-1 expression after phorbol 12-mristate acetate (PMA) stimulation [50]. A more detailed description of the transcription factor-mediated activation of LOX-1 is provided by Hermonat et al. [50].

Binding Ligands of LOX-1

While LOX-1 is particularly renowned for its binding to oxLDL [51], a diverse array of other ligands also bind LOX-1. As demonstrated by Ohki et al. [33], the LLR tripeptide motif within the CTLD plays a crucial role in selective ligand binding [40]. This binding surface exhibits a distinct charge distribution attributable to the “basic spine”: a linear alignment of basic arginine residues on the binding surface. Though acidic regions are present, they appear to have no influence on ligand binding. The basic spine generates a hydrophobic dimer surface due to phospholipid conjugation to lysine amino groups, which, in turn, favors the binding of negatively charged molecules [33]. Accordingly, LOX-1 primarily binds to oxLDL and other oxidized and acetylated forms of LDLs and apoptotic cells due to the negatively charged phosphatidylserine moieties on their surface, activated platelets, and polyanionic molecules such as heparin [33, 52‒55].

Furthermore, various proteins also serve as ligands in addition to modified LDLs: C-reactive protein (CRP), which is involved in the inflammatory response, and advanced glycation end-products (AGEs), known for causing hyperglycemic reactions [52, 55‒57]. LOX-1 can also form complexes with heat shock proteins HSP60 and HSP70 in dendritic cells, playing a role in antigen cross-presentation [30, 55, 58]. Additionally, molecules such as the 4-hydroxy-2-nonenal-histidine adduct, N-(4-oxononanyol)lysine (ONL), dextran sulfate, and cardiolipin are considered potential LOX-1 ligands [52, 53, 59, 60]. Also, different microbial pathogens could be LOX-1 ligands due to their upregulating effect on LOX-1. For Escherichia coli and Chlamydia pneumoniae, a binding to LOX-1 was already shown [61, 62]. However, the binding mechanism and to which bacterial compound LOX-1 is binding directly are still elusive. A list of known ligands is shown in Table 2. In summary, LOX-1 exhibits the capacity to bind to a diverse range of ligands, encompassing proteins, glycation end-products, and polyanionic molecules. While some binding sides for these ligands are already known, the complete binding capacity and specific binding sites of LOX-1 remain incompletely characterized, warranting further research.

Table 2.

List of reported ligands/regulators of LOX-1 activity and the regulatory effect (arrows), the binding site, and the references for each regulator

LigandRegulatory effetBinding siteReference
4-hydroxy-2-nonenal-histidine adduct ↑ [52
Activated platelets ↑ Cross-linking between LOX-1 expressing platelets [52, 55, 63
Advanced glycation end-products (AGEs) ↑ [52, 55
Angiotensin II ↑ [64
Apoptotic cells ↑ Negatively charged phosphatidyl serine, polyanion molecules [33, 52, 55
Cardiolipin and other phospholipids ↑ [52, 55
C-reactive protein ↑ [52, 55
HSP60 ↑ [52, 55
HSP70 ↑ [55
OxLDL and other acetylated LDLs ↑ Basic spine [33, 52, 55
Phorbol 12-myristate 13-acetate (PMA) ↑ [65
N-formylmethionyl-leucyl-phenylalanine (fMLP) ↑ [65
N-(4-oxononanyol)lysine (ONL) ↑ [52
Thapsigargin (THG) ↑ [65
Dithiotreitol (DTT) ↑ [65
TLR4 ↑ [66
NF-κB ↑ Gene promoter region [66
Fibronectin ↑ Similar to oxLDL? [55, 67
Aspirin ↓ Inhibition of superoxid anion generation [68
LOXIN ↓ Dimerization with LOX-1 [46
Poly [I] ↓ Similar to oxLDL? [53, 69
Dextran sulfate ↓ Similar to oxLDL? [53, 55, 69
Sodium salicylate ↓ Inhibition of superoxid anion generation [68
LigandRegulatory effetBinding siteReference
4-hydroxy-2-nonenal-histidine adduct ↑ [52
Activated platelets ↑ Cross-linking between LOX-1 expressing platelets [52, 55, 63
Advanced glycation end-products (AGEs) ↑ [52, 55
Angiotensin II ↑ [64
Apoptotic cells ↑ Negatively charged phosphatidyl serine, polyanion molecules [33, 52, 55
Cardiolipin and other phospholipids ↑ [52, 55
C-reactive protein ↑ [52, 55
HSP60 ↑ [52, 55
HSP70 ↑ [55
OxLDL and other acetylated LDLs ↑ Basic spine [33, 52, 55
Phorbol 12-myristate 13-acetate (PMA) ↑ [65
N-formylmethionyl-leucyl-phenylalanine (fMLP) ↑ [65
N-(4-oxononanyol)lysine (ONL) ↑ [52
Thapsigargin (THG) ↑ [65
Dithiotreitol (DTT) ↑ [65
TLR4 ↑ [66
NF-κB ↑ Gene promoter region [66
Fibronectin ↑ Similar to oxLDL? [55, 67
Aspirin ↓ Inhibition of superoxid anion generation [68
LOXIN ↓ Dimerization with LOX-1 [46
Poly [I] ↓ Similar to oxLDL? [53, 69
Dextran sulfate ↓ Similar to oxLDL? [53, 55, 69
Sodium salicylate ↓ Inhibition of superoxid anion generation [68

Proteolytic Regulation of LOX-1

LOX-1 activity and expression are subject to regulation through various mechanisms. Stimulation of LOX-1 expression can be elicited by diverse stimuli and ligands, including oxLDL, acute phase-inducing cytokines such as IL-1α/β, IL-6, TNF, and bacterial lipopolysaccharides, as well as other disease-associated factors [39].

The regulation of LOX-1 involves a range of mechanisms. One type of downregulating factor is microRNAs (miRNAs) that bind to and suppress LOX-1. Specific miRNAs like miRNA-98, miR-let-7g, and miR-590-5p directly interact with the 3′UTR regions of the OLR1 transcript, thereby reducing translation [39]. Additionally, the splice variant LOXIN functions as a direct inhibitor of LOX-1 by forming non-functional dimers with functional LOX-1 monomers. Another negative modulator of LOX-1 is Sirtuin-1 (SIRT1), a protein deacetylase that can inhibit the LOX-1-dependent formation of foam cells. This inhibition has been associated with a significant increase in plaque burden in ApoE-deficient mice [39].

The LOX-1 surface levels are further controlled through internalization. However, the underlying mechanisms are still elusive [39]. Furthermore, the surface level and signaling activity of LOX-1 are controlled through proteolytic cleavage by PMSF-sensitive proteases at two different cleavage sides which can occur through lysosomal degradation after internalization or via ectodomain shedding [39, 70]. Ectodomain shedding describes a proteolytic release of the protein’s ectodomain. In the case of LOX-1, this process generates soluble LOX-1 that is released into the extracellular compartment in humans as well as in the supernatant of bovine aortic endothelial cells (BAEC) [39, 70, 71]. For mice, it is not yet known whether sLOX-1 is produced. However, the necessary proteases seem to be available, as Mitsuoka et al. [72] showed that transgenic mice producing human LOX-1 can form soluble LOX-1. Various metalloproteinases, including those from the ADAM and MMP families, are potential candidates for LOX-1 shedding. A more comprehensive understanding of the proteolytic regulation processes of LOX-1 is detailed in the work of Mentrup et al. [39]. The process is described elsewhere. It was observed that the amount of free sLOX-1 in patients correlates with the severity of stroke and other cardiovascular events; therefore, sLOX-1 is a potential biomarker for detection of ischemic stroke in humans [70].

The outcome of lysosomal degradation and shedding of LOX-1 is the production of stable membrane-bound LOX-1 N-terminal fragments (NTF) of LOX-1. These NTFs function as regulators of LOX-1 signal transduction. Although the underlying mechanism still remains unclear, it is hypothesized that the cytosolic fragment might influence the transcription of target genes by migration to the nucleus [39].

LOX-1 is expressed across various cell types. An analysis of mRNA expression in different human cells conducted by The Human Protein Atlas proteinatlas.org version 22.0 (HPA) highlighted the highest LOX-1 expression in syncytiotrophoblasts, cytotrophoblasts, and macrophages. The LOX-1 expression of different cells is shown in Table 3 [21]. The processes in which LOX-1 is involved vary depending on the cell type and require further research.

Table 3.

LOX-1 mRNA expression in human cell types

Single cell typeCell typesnTPM
Syncytiotrophoblasts Trophoblast cells 463.1 
Cytotrophoblasts Trophoblast cells 399 
Macrophages Blood and immune cells 202.6 
Hofbauer cells Blood and immune cells 202.1 
Langerhans cells Blood and immune cells 79.5 
Microglial cells Glial cells 40.3 
Alveolar cells type 1 Specialized epithelial cells 28.9 
Alveolar cells type 2 Specialized epithelial cells 27.4 
Monocytes Blood and immune cells 21.3 
Kupffer cells Blood and immune cells 18.9 
Granulocytes Blood and immune cells 15.2 
Extravillous trophoblasts Trophoblast cells 14.6 
Early spermatids Germ cells 13.4 
Late spermatids Germ cells 11.6 
Fibroblasts Mesenchymal cell 10.9 
Endothelial cells Endothelial cells 10.8 
Respiratory ciliated cells Glandular epithelial cells 6.6 
Single cell typeCell typesnTPM
Syncytiotrophoblasts Trophoblast cells 463.1 
Cytotrophoblasts Trophoblast cells 399 
Macrophages Blood and immune cells 202.6 
Hofbauer cells Blood and immune cells 202.1 
Langerhans cells Blood and immune cells 79.5 
Microglial cells Glial cells 40.3 
Alveolar cells type 1 Specialized epithelial cells 28.9 
Alveolar cells type 2 Specialized epithelial cells 27.4 
Monocytes Blood and immune cells 21.3 
Kupffer cells Blood and immune cells 18.9 
Granulocytes Blood and immune cells 15.2 
Extravillous trophoblasts Trophoblast cells 14.6 
Early spermatids Germ cells 13.4 
Late spermatids Germ cells 11.6 
Fibroblasts Mesenchymal cell 10.9 
Endothelial cells Endothelial cells 10.8 
Respiratory ciliated cells Glandular epithelial cells 6.6 

The expression levels are shown as normalized transcripts per million (nTPM) for cell types with an expression higher than 6 nTPM (as retrieved from RNA-sequencing data in The Human Protein Atlas proteinatlas.org version 22.0 [21]). Created with BioRender.com.

Dendritic Cells

Dendritic cells (DC) are the antigen-presenting cells (APC) that present self and foreign antigens. This quality enables them to process signals from various cell types or pathogens, subsequently relying on differentiation cues to naïve T cells while eliciting cytotoxic responses [30, 73]. Among dendritic cells, human peripheral blood myeloid dendritic cells and macrophages were found to express LOX-1 as well as CD1c+ skin dermal DCs, but not human Langerhans cells or plasmacytoid DCs [30, 74]. As described by Huang et al. [75], the engagement of LOX-1 by oxLDL prompts the maturation of mouse bone marrow-derived DCs by activating the MAPK/NF-κB pathway.

LOX-1 also represents a receptor for Hsp70 in human peripheral blood myeloid cells. Additionally, LOX-1 seems to be involved in the transport of exogenous antigens through the MHC class I pathway and triggers cross-presentation on DCs. It has also been detected that LOX-1 can be a target for tumor antigens, inducing a protective CD8+ T-cell response with antitumoral function in mice [30]. Furthermore, targeting foreign and self-antigens to DCs via LOX-1 and DC-ASGPR leads to an antigen-specific CD4+ T-cell response producing IFN-γ [74, 76]. It has been suggested that LOX-1 could promote Th1 responses [74]. In addition, LOX-1 also functions as a DC signal for the uptake of apoptotic cells in IFN-α-conditioned DCs and induces T-cell immunity due to the presentation of apoptotic cell-derived antigens to CD4+ T helper cells and CD8+ T effector cells [77].

Furthermore, LOX-1 is the only CTLR reported to induce DCs to express a proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF), which leads to upregulated IgA and IgG responses. LOX-1 activation also elicits cytokines to promote B cell proliferation, differentiation, class-switching, and enhanced plasma cell survival. LOX-1-expressing DCs also stimulate naive B cells to enhance the expression of CCR10 and reduce CXCR5 levels, which allows B cells to migrate into mucosal sites. Moreover, these LOX-1-expressing DCs promote a differentiation of naïve B cells into plasmablasts [78].

Macrophages

LOX-1 is detected only in small amounts on undifferentiated human blood monocytes or THP-1 cells. However, after differentiation into macrophages, the cells express higher amounts of LOX-1 on their plasma membrane, where it can also function as an Hsp 70 receptor [30, 79]. The expression of LOX-1 can be upregulated by oxLDL uptake into mouse peritoneal macrophages. This also upregulates calpain-2 and downregulates calpain-1 expression. Calpain-1 and 2 are involved in integrin-mediated cell migration and are calcium-dependent. The deletion of LOX-1 decreases the amount of intracellular calcium and the amount of calpain-1 expression, which promotes macrophage migration. Therefore, calpains and LOX-1 seem to play a major role in macrophage migration. Due to a high uptake of oxLDL, LOX-1 can lead to impaired migration of macrophages, causing their arterial retention and foam cell formation, thus supporting the development of atherosclerosis [80]. The formation of foam cells is further supported by reactive oxygen species, resulting from the oxidation of LDL-cholesterol to oxLDL. This leads to the upregulation of oxidative stress in macrophages. This mechanism also appears to involve NOX enzymes and the phosphorylation of MAPKs. However, the exact mechanism is still unknown [81].

Neutrophils

The expression of LOX-1 in neutrophils appears to be induced under different conditions. While healthy human donors show little-to-no OLR1 expression in neutrophils of the peripheral blood, 15–50% of neutrophils in tumor tissues express LOX-1. Neutrophils positive for LOX-1 show similar biochemical characteristics to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), such as upregulated endoplasmic reticulum (ER) stress and potent immunosuppressive activity. Further experiments showed that an induction of ER stress in neutrophil leads to the expression of LOX-1 and a subsequent transformation of these neutrophils into suppressive PMN-MDSCs. These transformed cells have the ability to suppress T-cell function [65]. To be more precise, LOX-1 inhibits the CD3+ T-cell proliferation involving ARG1 and iNOS [82]. However, while human LOX-1 represents a marker for PMN-MDSCs, it is not clear whether LOX-1 is directly involved in these mechanisms [65].

Mouse LOX-1 does not associate with PMN-MDSCs, suggesting different mechanisms in the regulation of LOX-1 in mice compared with humans [65]. Another immunoregulatory effect induced by LOX-1 in mice involves an overreaction of neutrophils in sepsis. The inhibition of murine LOX-1 dampened neutrophil activation and therefore allowed better control and increased recruitment of neutrophils to the infected tissue. This also led to more effective bacterial clearance. In septic mice, an excessive neutrophil response led to reduced surface expression of CXCR2, leading to impaired neutrophil migration. Therefore, LOX-1 on murine neutrophils seems to play a major role in the dysfunction of inflammatory and immune responses during sepsis [83].

Furthermore, it has been shown that neutrophil extracellular traps (NETs) utilize oxidative enzymes to oxidize surrounding materials including LDL. This process leads to an increased presence of oxLDL, resulting in heightened stimulation of LOX-1 in tumor endothelial cells [65, 84].

B Cells

LOX-1 is expressed on human B cells and takes part in the humoral response. It stimulates B cells to upregulate the expression of CCR7 which is an important factor in B cell migration into lymphoid tissues [78]. Despite the ability of LOX-1 to stimulate B cell migration, little is known about the signaling cascade being activated in B cells due to LOX-1 activation. Further investigations are needed to better understand the mechanisms of LOX-1 in B cells.

Platelets and Fibroblasts

LOX-1 is expressed on the surface of platelets and megakaryocytic cells upon activation with oxLDL. Due to its ability to recognize other LOX-1-expressing platelets, they cross-link and aggregate. On the one hand, this mechanism leads to an accumulation of activated platelets in an injured epithelium, aiding in the closure of damaged blood vessels. On the other hand, LOX-1-expressing platelets, along with their fast delivery to lesions, may also contribute to pathological changes in blood vessels, and the cross-linking can lead to the formation of stable thrombi [63].

Furthermore, LOX-1 is involved in the aging process of fibroblasts as it downregulates aging-related proteins. The deletion of LOX-1 leads to a significant change in F-actin distribution, massive growth of fibroblasts, and impaired mitosis. It was further discovered that LOX-1 transfection into LOX-1-deleted fibroblasts partially restored CDC42, which is a regulator of cell division and cytoskeleton organization, and P70 S6 kinase expression, resulting in reorganization of F-actin in senescent fibroblasts. A functional LOX-1 also restores fibroblast morphology and mitotic activity. Therefore, LOX-1 appears to be important for the integrity of the cytoskeleton [85].

Endothelial Cells

Sawamura et al. [24] initially described LOX-1 as a receptor for oxLDL in the vascular endothelium. Since then, many functional implications of the receptor have been described in this tissue type. A study by Oka et al. [53] showed that LOX-1 expressed on endothelial cells recognizes anionic phospholipids, such as phosphatidylserine (PS), that are expressed on the plasma membrane due to apoptosis and aging. The presence of PS on the cell surface allows LOX-1 to bind these apoptotic cells. The inhibition of LOX-1 caused the inhibition of the majority of phagocytosis, leading to the conclusion that LOX-1 appears to be directly involved in the phagocytic process.

More specifically, LOX-1 appears to mediate the phagocytic pathway as a receptor, recognizing early stages of the apoptotic process by binding to PS. This binding of PS-expressing cells could be important for the cardiovascular system, as these cells promote blood coagulation. Therefore, the degradation of these cells is important to maintain the blood in an anticoagulant state [53]. In addition, oxLDL exposure to HUVECs induces a LOX-1-mediated increase of global DNA methylation. This leads to a lower activation of apoptosis-relevant genes, resulting in resistance against LOX-1-mediated apoptosis [86].

The binding of vascular epithelial cells to extracellular matrix proteins, such as fibronectin, is important for cell migration and various cellular functions. LOX-1 has been demonstrated to support cell adhesion to fibronectin, thus playing a role in various pathophysiological contexts such as inflammation and atherogenesis [69]. This involvement is mediated by various mechanisms including the LOX-1-regulated production of proinflammatory cytokines such as TNF and IL-1 in endothelial cells in septic mice (an atherosclerotic model) [83].

As LOX-1 has been associated with cancer, it was shown that inhibition of LOX-1 in tumor endothelial cells reduces lung metastasis and tumor endothelial cell proliferation. In addition, endothelial cells expressing LOX-1 were able to upregulate the migration of neutrophils to endothelial cells through CCL2 secretion from tumor endothelial cells. Additionally, these LOX-1-overexpressing endothelial cells attract neutrophils through the secretion of cytokines such as IL-6 or IL-8 [84]. LOX-1 also increases the trans-endothelial transfer of oxLDL due to the mediated downregulation of desmosomal cell-cell contacts, which results in weakened endothelial junctions [67].

Smooth Muscle Cells

LOX-1 is also expressed on vascular smooth muscle cells (VSMCs) and plays a major role in plaque formation and atherosclerosis. While oxLDL generates ROS in VSMCs, which is associated with high oxidative stress levels, it also induces apoptosis in VSMCs [87, 88]. The reduction of ROS by radical-scavenging agents (catalase, deferoxamine, NAC) also prevents apoptosis, suggesting a link between apoptosis and oxLDL [87, 88]. Apoptosis is dependent on LOX-1, which mediates the uptake of oxLDL. After uptake, oxLDL induces apoptosis in a Bax/Bcl-2-dependent pathway, involving the downregulation of Bcl-2 and activation of caspase 3 [87].

The first studies of LOX-1 showed that mainly the aortic intima and organs with a rich vascular supply express LOX-1 mRNA [24]. These organs include the placenta, lungs, brain, and liver. The Human Protein Atlas (HPA) [21] presents a similar expression pattern of LOX-1 in human organs, as indicated by diverse sources of RNA-seq data. As shown in Figure 9, LOX-1 expression varies across different human organs, with its highest expression observed in the retina, brain, placenta, and lungs (Fig. 9). In comparison to the expression of PRRs, LOX-1 exhibits much higher expression in most organs than, for example, Dectin-1, TLR 2, TLR 4, and TLR 6, as measured by the normalized TPM values reported in the HPA project [21]. The subsequent sections will elaborate on the organ-specific functions of LOX-1.

Fig. 9.

Schematic representation of the LOX-1 mRNA expression in human organs. The expression levels are shown as normalized transcripts per million (nTPM) for all organs with an expression higher than 6 nTPM (as retrieved from RNA-sequencing data in The Human Protein Atlas, proteinatlas.org, version 22.0 [20]). Created with BioRender.com.

Fig. 9.

Schematic representation of the LOX-1 mRNA expression in human organs. The expression levels are shown as normalized transcripts per million (nTPM) for all organs with an expression higher than 6 nTPM (as retrieved from RNA-sequencing data in The Human Protein Atlas, proteinatlas.org, version 22.0 [20]). Created with BioRender.com.

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Eye (Retina)

LOX-1 expression in the eye can be triggered through various pathways. Research has demonstrated that a laser-induced injury of the retina results in upregulation of LOX-1 mRNA and induces inflammatory changes in the vascular endothelium. In animal eyes, inhibiting LOX-1 has been shown to reduce inflammation by decreasing the adhesion of circulating leucocytes to the vascular endothelium of the retina. LOX-1-deficient mice also exhibit inhibition of choroidal neovascularization, the abnormal growth of new blood vessels beneath the retinal pigment epithelium following the laser-induced retinal injury. These findings suggest that LOX-1 plays a significant role in the inflammatory response within the eye [89].

Furthermore, another investigation involving LOX-1 in the retinal veins of female Lewis rats challenged with lipopolysaccharides (LPS) demonstrated that inhibition of LOX-1 led to suppression of leukocyte infiltration [90]. However, specific signaling pathways through which LOX-1 operates in the context of eye infections remain as of yet unknown.

Brain

In the context of the brain, LOX-1 has been predominantly studied in the setting of acute ischemic stroke. OxLDL triggers increased vascular inflammation and permeability by activating LOX-1 in primary human male microvascular endothelial cells. Conversely, inhibition of LOX-1 in these cells has demonstrated a beneficial outcome in terms of cerebrovascular endothelial permeability and inflammation [91].

LOX-1’s upregulation was additionally observed in the neonatal hypoxic-ischemic encephalopathic (nHIE) rat brain, as well as microglia from human nHIE brains [92, 93]. Administration of anti-LOX-1 antibodies to nHIE rats resulted in an improvement of brain pathology, solidifying LOX-1 as a potential candidate for nHIE treatment. The expression of LOX-1 in microglial cells from newborn rats increased in response to hypoxic and ischemic conditions [92]. Suppression of LOX-1 in these cells led to a reduction in inflammatory mediators along with suppressed microglial activation and proliferation [92, 93]. A study by Aoki et al. [92] further suggested that microglial cells might possess an inducible immune system activated under hypoxic and ischemic conditions. This response is influenced by HIF-α and NF-κB, which directly control LOX-1 expression. Additionally, MAPKs are directly implicated in LOX-1 activation, and research by Ge et al. [94] implies a positive feedback loop involving LOX-1/MAPKs/NF-κB that contributes to microglial activation. Further studies have revealed that neuronal damage, LPS, and HSP60 can promote LOX-1 expression in rat microglia as well [94, 95].

Additionally, studies involving LOX-1-knockout rats with a genetic SHRSP background, a stroke animal model, have shown a reduced occurrence of spontaneous brain damage following cerebral ischemia. Further investigation indicated that LOX-1 might play a role in the pathophysiological disruption of the blood-brain barrier after cerebral ischemia [96].

Placenta

A significant overexpression of LOX-1 is evident in the placenta. LOX-1’s active involvement in the early stages of pregnancy is suspected, particularly during the rising oxidative stress in the placenta at the end of the first trimester. However, while LOX-1 is prominently expressed, it does not appear to fulfill an indispensable role. This conclusion is drawn from observations with LOX-1 knockout mice which displayed fertility and avoided complications such as miscarriage. Although LOX-1 is commonly found in vascular epithelial cells, it is not identified in these cells within the mouse placenta. Instead, LOX-1 appears to play a role in trophoblast invasion during early pregnancy as well as increased apoptosis of trophoblasts in cases of preeclampsia [97]. In the context of preeclampsia, the implication of LOX-1 remains a subject of debate in the scientific literature. Chigusa et al. [98] reported a decreased expression of LOX-1 and Nrf2 expression, while Lee et al. [99] observed an increased expression of LOX-1 in the placenta during preeclampsia. Furthermore, women with conditions such as hypercholesterolemia or diabetes mellitus have been noted to exhibit elevated LOX-1 protein expressions in the placenta [100].

Lung

As shown in Figure 9, the lung is one of the primary sites of LOX-1 expression. Here, LOX-1 is mainly localized in alveolar macrophages and neutrophils. During pneumonia, LOX-1 expression in the lung is upregulated, resulting in increased neutrophil recruitment and heightened antibacterial defense. Korkmaz et al. have described that LOX-1 exerts a dampening effect on local immune signaling during pneumonia in mice, attributed to the downregulation of proinflammatory factors such as cytokines. Furthermore, LOX-1 accumulation seems to be driven by hematopoietic cells [101]. This dampening effect of LOX-1 on immune signaling contrasts with prior inflammation models of LOX-1 which linked upregulation of LOX-1 with an enhanced inflammatory response and greater tissue damage in mouse lungs [83, 101, 102]. In contrast, the inhibition of LOX-1 in this study led to dysregulation and an increased inflammatory response in mice. This suggests that LOX-1 is a tissue-protective factor in the pulmonary environment [101]. The reason for this discrepant effect of LOX-1 is not yet known and warrants further investigation.

Cardiovascular System

LOX-1 has been extensively studied in the context of cardiovascular disease as it serves as a major receptor for oxLDL and holds a critical role in the pathophysiology of atherosclerosis: high levels of LOX-1 expression are associated with the promotion of various cardiovascular pathological processes: atherosclerotic plaque formation, myocardial ischemia, fibrosis, and stroke. However, the underlying regulatory pathways are not fully understood. Some correlations are already known, as illustrated in Figure 1. A detailed overview is given elsewhere [27, 103].

In addition, LOX-1 appears to play a role in sickle cell anemia. Sickle-shaped red blood cells bind to endothelial cells, leading to an upregulation of LOX-1 expression. Furthermore, elevated levels of soluble LOX-1 have been reported in the plasma of individuals with sickle cell disease. This suggests that LOX-1 could potentially function as an adhesion molecule for sickled red blood cells, potentially contributing to the pathogenesis of sickle cell anemia [104].

Liver

In the context of the mouse model of non-alcoholic fatty liver disease (NAFLD), LOX-1 has been found to be involved in activating hepatic stellate cells, thereby triggering hepatic fibrogenesis. In cases of non-alcoholic steatohepatitis, LOXIN is associated with disease severity and concurrently modulates insulin sensitivity and β cell function in humans. Furthermore, it appears to regulate plasma adipokines and hepatocyte apoptosis in both diseased and healthy individuals [105]. Overexpression of LOXIN in mice also appears to have a protective effect against atherosclerosis and promotes liver tissue regeneration [106]. Furthermore, it was discovered that persistent ectopic expression of LOX-1 in the livers of mice leads to the binding and degradation of circulating oxLDL, thereby preventing the progression of atherosclerosis through the expression of cholesterol transporters [107].

LOX-1 Signaling Pathways and Its Effects

In contrast to other C-type lectins, the signaling pathways of LOX-1 remain largely unexplored. Presently, primarily different interaction partners are known, although the precise nature of these interactions remains unclear. The recognized interactions, significant in cardiovascular diseases, are illustrated in Figure 1. Metabolites such as oxLDL, AGEs, angiotensin II, and cytokines, along with shear stress, upregulate LOX-1 expression. This leads to the generation of various proinflammatory factors, resulting in platelet aggregation, angiogenesis, fibrosis, and endothelial dysfunction, among other effects [27, 64, 103]. While some signaling pathways, as depicted in Figure 1, are partially known, LOX-1 also appears to be implicated in other processes such as the infection response, cancer, and other diseases. Currently, no specific signaling pathway is yet known for LOX-1 in infectious processes or the infection response. As illustrated in Figure 10, a few bacterial, viral, and fungal components are known to upregulate the LOX-1 expression, which subsequently triggers the release of various metalloproteinases, cytokines, integrins, selectins, and other metabolites (as detailed later) (Fig. 10). A compilation of known interaction partners of LOX-1 in infections can be found in Table 4. These primarily comprise factors recognized from inflammatory and other immune-relevant processes. In addition, TLR4 and NFκB also appear to play supportive roles in some LOX-1 signaling pathways [66]. However, some possible signaling pathways can be deduced from the previously known interactions of LOX-1 with other immune-relevant factors, which are shown in Figure 11 (Fig. 11). As shown by Mattaliano et al. [116], the signaling process could involve ROCK2 and ARHGEF1, as these are recruited to the LOX-1 receptor complex after oxLDL treatment of endothelial cells. ROCK2 and ARHGEF1 are both involved in Rho signaling. It should be noted, however, that it is not known how LOX-1 signaling reaches the activation of the individual mechanisms.

Fig. 10.

Summary of the known interactions of LOX-1 with infectious agents (fungi, viruses, and bacteria). Shown are the reported activating particles/pathways (arrows to the receptor) and the known effector mechanisms and induced downstream mediators/proteins (arrows from the receptor). Fungal activators/mechanisms are depicted on a green background, bacterial ones on an orange background, and viral proteins on a purple background. Effector molecule functions are color-coded, while frame intensities indicate the consistency of the finding in the literature (number of times reported). Created with BioRender.com.

Fig. 10.

Summary of the known interactions of LOX-1 with infectious agents (fungi, viruses, and bacteria). Shown are the reported activating particles/pathways (arrows to the receptor) and the known effector mechanisms and induced downstream mediators/proteins (arrows from the receptor). Fungal activators/mechanisms are depicted on a green background, bacterial ones on an orange background, and viral proteins on a purple background. Effector molecule functions are color-coded, while frame intensities indicate the consistency of the finding in the literature (number of times reported). Created with BioRender.com.

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Table 4.

List of the agents interacting with LOX-1 in infections and in which cell and animal models the interaction was reported

Interacting agentAnalyzed modelEffectEffect detected throughReference
LPS Mouse LOX-1 stimulating target Protein, mRNA [50, 88, 100, 107
ICAM-1 Mouse, human microvascular endothelial cells (HMEC-1), HUVECs, RAW macrophages, mouse corneas Upregulation, mediated by NF-κB Protein, mRNA [50, 108‒111
Glycan HMEC-1, RAW macrophages LOX-1 stimulating target Protein [109
TLR4 BMCs, HUVECs LOX-1 stimulating target, mediated by MAPK mRNA [62, 112, 113
TLR2 BMCs LOX-1 stimulating target, mediated by MAPK mRNA [114
GroEL Mouse macrophages, CHO cells, HCAECs, rabbits LOX-1 stimulating target, mediated by TLR4 or Rac1 Protein [61, 62, 112
PI3k/Akt-mediated eNOS HCAECs LOX-1 stimulating target Protein [62
NADPH oxidase HCAECs LOX-1 stimulating target Protein [62
MAPK-Pathway HCAECs LOX-1 stimulating target Protein [62, 108
MMP-2 Human macrophages Upregulation Protein [113, 115
MMP-3 HMEC-1, HUVECs, RAW macrophages Upregulation Protein [116
NO Endothelial cells Downregulation of the release [117
Superoxid anion Endothelial cells Upregulation of the release [117
MMP-1 HMEC-1, HUVECs, RAW macrophages Upregulation Protein [109
CCR2 THP-1 Upregulation, mediated by NF-κB Protein, mRNA [110
αMβ2 THP-1 Upregulation, mediated by NF-κB Protein, mRNA [110
MCP-1 HUVECs, human corneal epithelial cells, mouse corneas Upregulation, mediated by NF-κB Protein, mRNA [110, 113
IL-1β Human corneal epithelial cells, mouse corneas Upregulation Protein, mRNA [113
VCAM-1 HMEC-1, HUVECs, RAW macrophages, mouse corneas Upregulation Protein, mRNA [111, 112, 118
E-Selectin HMEC-1, HUVECs, RAW macrophages, mouse corneas Upregulation, mediated by NF-κB Protein, mRNA [109‒111
ATF4 Mouse corneas, HCECs Upregulation, mediated by ERK1/2, TLR4, JNK Protein [119
MMP-9 Mouse macrophages, mouse neutrophils Upregulation mRNA [120
CXCL1 Mouse macrophages, mouse neutrophils Upregulation mRNA [120
IL-10 Mouse macrophages, mouse neutrophils Upregulation mRNA [120
IL-6 Mouse macrophages, mouse neutrophils Upregulation mRNA [120
TNF Mouse macrophages, mouse neutrophils, mouse endothelial cells Upregulation in context with E. coli, fungi and polymicrobial sepsis model Protein, mRNA [49, 65, 120‒122
P-Selectin Mouse corneas Upregulation mRNA [111
LFA-1 Mouse corneas Upregulation mRNA [111
HMGB1 (BoxB) Mouse macrophages, mouse neutrophils LOX-1 stimulating target Protein, mRNA [111
Unknown virus particles Diverse human and animal cell types Protein, cDNA [114, 118, 120, 123‒128
Interacting agentAnalyzed modelEffectEffect detected throughReference
LPS Mouse LOX-1 stimulating target Protein, mRNA [50, 88, 100, 107
ICAM-1 Mouse, human microvascular endothelial cells (HMEC-1), HUVECs, RAW macrophages, mouse corneas Upregulation, mediated by NF-κB Protein, mRNA [50, 108‒111
Glycan HMEC-1, RAW macrophages LOX-1 stimulating target Protein [109
TLR4 BMCs, HUVECs LOX-1 stimulating target, mediated by MAPK mRNA [62, 112, 113
TLR2 BMCs LOX-1 stimulating target, mediated by MAPK mRNA [114
GroEL Mouse macrophages, CHO cells, HCAECs, rabbits LOX-1 stimulating target, mediated by TLR4 or Rac1 Protein [61, 62, 112
PI3k/Akt-mediated eNOS HCAECs LOX-1 stimulating target Protein [62
NADPH oxidase HCAECs LOX-1 stimulating target Protein [62
MAPK-Pathway HCAECs LOX-1 stimulating target Protein [62, 108
MMP-2 Human macrophages Upregulation Protein [113, 115
MMP-3 HMEC-1, HUVECs, RAW macrophages Upregulation Protein [116
NO Endothelial cells Downregulation of the release [117
Superoxid anion Endothelial cells Upregulation of the release [117
MMP-1 HMEC-1, HUVECs, RAW macrophages Upregulation Protein [109
CCR2 THP-1 Upregulation, mediated by NF-κB Protein, mRNA [110
αMβ2 THP-1 Upregulation, mediated by NF-κB Protein, mRNA [110
MCP-1 HUVECs, human corneal epithelial cells, mouse corneas Upregulation, mediated by NF-κB Protein, mRNA [110, 113
IL-1β Human corneal epithelial cells, mouse corneas Upregulation Protein, mRNA [113
VCAM-1 HMEC-1, HUVECs, RAW macrophages, mouse corneas Upregulation Protein, mRNA [111, 112, 118
E-Selectin HMEC-1, HUVECs, RAW macrophages, mouse corneas Upregulation, mediated by NF-κB Protein, mRNA [109‒111
ATF4 Mouse corneas, HCECs Upregulation, mediated by ERK1/2, TLR4, JNK Protein [119
MMP-9 Mouse macrophages, mouse neutrophils Upregulation mRNA [120
CXCL1 Mouse macrophages, mouse neutrophils Upregulation mRNA [120
IL-10 Mouse macrophages, mouse neutrophils Upregulation mRNA [120
IL-6 Mouse macrophages, mouse neutrophils Upregulation mRNA [120
TNF Mouse macrophages, mouse neutrophils, mouse endothelial cells Upregulation in context with E. coli, fungi and polymicrobial sepsis model Protein, mRNA [49, 65, 120‒122
P-Selectin Mouse corneas Upregulation mRNA [111
LFA-1 Mouse corneas Upregulation mRNA [111
HMGB1 (BoxB) Mouse macrophages, mouse neutrophils LOX-1 stimulating target Protein, mRNA [111
Unknown virus particles Diverse human and animal cell types Protein, cDNA [114, 118, 120, 123‒128

Also described is the effect of the agent on LOX-1 or vice versa, and whether the interaction was determined at protein or transcriptional level. Furthermore, the list contains the respective references to the papers in which the interaction was described.

Fig. 11.

Illustration of possible signaling pathways of LOX-1. Shown are the activation of MAPK-pathways [129‒131], NF-κB pathways [39, 129‒131], Calpain-modulation [129], apoptosis-pathways [129, 132], and others [20, 39, 129, 130], leading to the already known effects of LOX-1: enhancement of macrophage migration, endothelial dysfunction, apoptosis, autophagy, inflammation, VSMC migration, and monocyte infiltration, as described in the literature. It is known that LOX-1 uses ROCK2 and ARHGEF1 for signaling, but the exact mechanisms are unknown. These unknown activation mechanisms are shown in dashed lines. OxLDL is shown as the best known ligand of LOX-1, for LOX-1 activation. Created with BioRender.com.

Fig. 11.

Illustration of possible signaling pathways of LOX-1. Shown are the activation of MAPK-pathways [129‒131], NF-κB pathways [39, 129‒131], Calpain-modulation [129], apoptosis-pathways [129, 132], and others [20, 39, 129, 130], leading to the already known effects of LOX-1: enhancement of macrophage migration, endothelial dysfunction, apoptosis, autophagy, inflammation, VSMC migration, and monocyte infiltration, as described in the literature. It is known that LOX-1 uses ROCK2 and ARHGEF1 for signaling, but the exact mechanisms are unknown. These unknown activation mechanisms are shown in dashed lines. OxLDL is shown as the best known ligand of LOX-1, for LOX-1 activation. Created with BioRender.com.

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Another study demonstrated that knockdown of OLR1 causes autophagy-associated cell death of esophageal cancer cells due to the induction of dephosphorylation of TFEB S142 and therefore promotion of TFEB nuclear localization. The study further found OLR1 to be coupled with the intracellular adapter protein RACK1 which promotes the signaling of RAS-MAP2K/MEK-MAPK/ERK for TFEB-dependent autophagy inhibition [133]. Consequently, it appears that LOX-1 signaling has the capacity to regulate autophagy.

Since LOX-1 is increasingly being recognized as a player in the initiation of proinflammatory immune responses, evidence is accumulating that LOX-1 may also serve as an important receptor in the context of infectious disease pathogens. In this context, direct recognition of PAMPs is also possible. In recent years, a link between the upregulation of LOX-1 and various bacterial, viral, and fungal infections has also been established. This will be discussed in more detail in the next sections. The currently known interactions with pathogens are further summarized in Figure 10.

LOX-1 Interactions with Gram-Positive Bacteria

Staphylococcus aureus and Streptococcus pneumoniae are so far the only gram-positive bacteria for which an interaction with LOX-1 has been demonstrated [61, 101]. Shimaoka et al. [61] described LOX-1 to support adhesion of S. aureus, but the binding was not associated with the induction of TNF-secretion in the LOX-1-expressing cells. Further, Korkmaz et al. [101] reveal an increase of LOX-1 induction and sLOX-1 levels in the pneumatic left lung lobes of mice upon S. pneumoniae infection. There is, as of yet, no data about the detailed interaction of Gram-positive bacteria and LOX-1.

LOX-1 Interactions with Gram-Negative Bacteria

In contrast to Gram-positive bacteria, there is much more evidence regarding the interaction of LOX-1 with Gram-negative bacteria. LPS, a component of the cell wall of Gram-negative bacteria, has been shown to increase the expression of LOX-1 and ICAM-1 [102, 134]. Moreover, inhibition of LOX-1 signaling was shown to prevent an inflammatory response to LPS [102]. Based on these findings, LOX-1 seems to regulate the inflammation induced by LPS; however, it is still unclear whether there is a direct interaction.

E. coli

Shimaoka et al. [61] showed that E. coli can bind to cells expressing LOX-1. Furthermore, the authors demonstrated that the expression of LOX-1 and thus the binding of E. coli to LOX-1-expressing cells increase as a result of stimulation with TNF. GroEL seems to be significantly involved in the adhesion of E. coli to LOX-1. It was shown that the expression of GroEL on the surface of E. coli contributed to an enhancement of the binding of E. coli to macrophages. In addition, overexpression of GroEL on the surface of E. coli led to mice being more susceptible to infection [117].

According to Molina et al. [121], the local neutralization of LOX-1 in mice lungs infected with E. coli led to an increase of injured tissue and cytokine release. This could be an indication of a protective effect of LOX-1 on pneumonia. However, systemic inhibition of LOX-1 did not show a significant effect on the injury of lung tissue, the recruitment of leukocytes, or apoptosis [101].

C. pneumoniae

C. pneumoniae infections are described to play a pathogenic role in atherosclerosis, potentially through their ability to upregulate LOX-1 expression [62, 112]. Interestingly, in the context of C. pneumoniae infection, the expression of LOX-1 seems not to be upregulated by TNF or angiotensin II in HUVECs [108]. Instead, Lin et al. [135] showed that the heat shock protein 60 (GroEL1) of C. pneumoniae induces LOX-1 expression in HCAECs via TLR4 mediation [42]. Furthermore, the increase of LOX-1 expression leads to an upregulation of E-selectin, MMP-1, MMP-3, ICAM-1, and VCAM-1 [112]. Additionally, NADPH oxidase activation, MAPK signaling, PI3K/Akt-mediated PI3K activation, and Rac1 seem to be involved in the LOX-1 upregulation [42, 135]. Further analyses by Sun et al. [136] described the interaction more precisely. In this study, LOX-1 expression induced by C. pneumoniae infection was activated by the MAPK superfamily member ERK1/2 but not by p38 MAPK and JNK. Moreover, the activation of the peroxisome proliferator-activated receptor gamma (PPARγ) by rosiglitazone reduced LOX-1 expression. PPARγ regulates the lipid metabolism through gene transcription and binds to MEK1, which is a kinase upstream of ERK1/2, and therefore reduces LOX-1 expression [109, 136]. In addition, fluvastatin is able to reduce the expression of LOX-1 in chlamydia-infected SMCs [110].

Furthermore, a study by Campbell et al. [62] suggested that in addition to upregulating LOX-1, C. pneumoniae is able to directly bind the LOX-1 receptor, which, during the infection, is mainly expressed in lung tissue and the aorta. Therefore, the glycan of C. pneumoniae has been suggested as a potential LOX-1 ligand, as the absence of this glycan results in the relapse of the pathogen-induced upregulation of LOX-1 [112]. Anti-LOX-1 antibodies inhibit the binding of C. pneumoniae to LOX-1 and further inhibit infectivity [62]. However, the direct link between the induction pathways and the interactions must be analyzed further to understand the full mechanism of LOX-1-mediated regulation.

The involvement of C. pneumoniae infection in atherosclerosis is unique among chlamydial pathogens [62, 112]. While C. pneumoniae can be found in atherosclerotic lesions, Chlamydia trachomatis infection seems not to induce atherosclerosis or plaque development and was not detected in atheromas. Further, inhibition of C. trachomatis infection due to anti-LOX-1 antibodies was not detected, and C. trachomatis did not bind to LOX-1 [62]. Therefore, the specific interaction of LOX-1 and C. pneumoniae seems to be unique for chlamydial pathogens.

Porphyromonas gingivalis

P. gingivalis is mainly known as a periodontal bacterium and is often involved in peri-implantitis. Recently, P. gingivalis has been shown to upregulate the expression of LOX-1 in HUVEC and THP-1 cells. LOX-1 is thereby involved in the cell migration of THP-1 and adhesion to HUVECs [115]. Similar to C. pneumoniae and E. coli, GroEl was found to upregulate LOX-1, TLR4, VCAM-1, and ICAM-1 expression in infected HCAECs and the aorta of hypercholesterolemic mice [114]. Furthermore, LOX-1 was found to upregulate the expression of ICAM-1, MCP-1, E-Selectin in infected HUVECs and integrin αMβ2, CCR2 in infected THP-1 cells, which also were dependent on NF-κB activation [115]. Also, matrix metalloproteinase-2 (MMP-2) was found to be upregulated by LOX-1 in human macrophages infected by P. gingivalis. In this process, JNK and ERK1/2 also seemed to be involved in the LOX-1-dependent signaling process [113]. Additionally, it was found that LOX-1 is upregulated during infection in a process mediated by TLR2 and/or activation via MAPK in BMCs, which leads to osteoclastogenesis [123]. Zhang et al. [124] described that the wingless-type MMTV integration site family member 5A (Wnt5a), which is a glycoprotein mediating signal transduction, seems to be involved in the TLR4 and LOX-1-mediated inflammatory response during peri-implantitis. It further upregulates the expression of IL-1β, chemokine MCP-1, and MMP-2. In summary, the literature provides strong evidence for the involvement of LOX-1 in inflammation in response to P. gingivalis infection. While it is not known if LOX-1 can be activated by a direct interaction with P. gingivalis, several processes are triggered that are able to upregulate LOX-1, such as the upregulation of TLR4 [123]. Furthermore, LOX-1 triggers the release of various integrins, metalloproteinases, and selectins [115]. The exact signaling pathways triggered by LOX-1 are not yet known, although MAPK and NF-kB seem to be involved [115, 123]. Further research is still needed to understand the LOX-1-mediated infection response to P. gingivalis.

Virus

Associations between viral infection and an upregulating effect on LOX-1 expression have been found for various ssRNA and dsDNA viruses. Notably, there have been no studies on dsRNA viruses so far.

ssRNA Viruses

One of the more prominent ssRNA viruses is SARS-CoV-2 which is associated with thromboembolic effects. In the context of severe SARS-CoV-2 infection, a clinical study showed that the bronchoalveolar space in the lungs of these patients is infiltrated by immature neutrophils expressing LOX-1. Besides LOX-1, CD123 and PD-L1 were also expressed by immature neutrophils (ImNs). The expression levels of all three receptors on ImNs correlated with disease severity. However, only the LOX-1-expressing ImNs were associated with the thromboembolic effects of the SARS-CoV-2 infection due to the secretion of different proinflammatory cytokines, including IL-6, TNF, and IL-1β. The authors suggest that LOX-1 is overexpressed in systemic inflammatory diseases due to the highly oxidative environment [118]. However, it is not clear if thrombolytic events are caused by the LOX-1-expressing ImNs or by other LOX-1-expressing cells, that may not be directly linked to SARS-CoV-2 [118]. Furthermore, Coudereau et al. [125] showed that COVID-19 patients with ARDS showed increased levels of LOX-1-expressing neutrophils with myeloid-derived suppressor cell (MDSC) phenotype. MDSCs are known for their immunosuppressive function due to the suppression of T cells [126]. The upregulation of LOX-1-expressing MDSCs raises the question of whether LOX-1 could be involved in the suppression of the immune response during SARS-CoV-2 infections. This is yet to be examined.

The ssRNA virus influenza virus A (H1N1) is hypothesized to cause thrombosis, leading to multiple-organ dysfunction [137]. A study by Ohno et al. [137] showed that during a severe influenza infection in a mouse model, thrombin generation is increased and LOX-1 expression in the aorta is upregulated in contrast to LOX-1 knockout mice. It was suggested that LOX-1 is involved in the early thrombus formation in severe influenza infections.

Another virus associated with LOX-1 is the human immunodeficiency virus (HIV). Patients living with HIV display increased rates of atherosclerosis. A study by Hag et al. [138] indicated an upregulation of LOX-1 in the aortic arch in HIV-1Tg rats, representing an HIV-animal model. They suggested a connection between HIV and the expression of LOX-1.

In summary, LOX-1 upregulation during infections with ssRNA viruses seems to be associated with a higher occurrence of atherosclerosis. However, it is not yet known whether this is a side effect of the immune response to the viral infection or if the virus can directly trigger upregulation of LOX-1. Further research is needed to clarify these mechanisms.

dsDNA Viruses

An association between viral infections and the increased incidence of atherosclerosis has also been observed for various dsDNA viruses. Different studies, for example, by Kotronias et al. [127], have demonstrated an association between Herpes simplex virus-1 (HSV-1) infection and coronary atherosclerosis. As described by Chirathaworn et al. [122], HSV-1 induces an upregulation of LOX-1 in infected epithelial cells. They suggest that HSV-1 contributes to atherogenesis through the upregulation of LOX-1 expression.

Infections with human cytomegalovirus (HCMV) have also been shown to induce cardiovascular diseases such as myocardial infarction. HCMV is a major risk factor for atherosclerosis [120, 139]. Li et al. [120] found that carotid atherosclerotic patients with an HCMV infection exhibit significantly increased levels of MMP-9, TNF, and LOX-1 in the blood serum in comparison to uninfected individuals. Despite the positive correlation between HCMV infection and LOX-1 upregulation, little is known about the interaction.

A different effect of LOX-1 was observed in chronic hepatitis B (CHB) infection, where PMN-MDSCs have been shown to suppress the virus-specific T-cell response [128, 140]. Li et al. [140] demonstrated that PMN-MDSCs expressed by CHB patients who have survived nasopharyngeal carcinoma (NPC) exhibit higher levels of LOX-1 than NPC survivors without CHB. The level of expressed LOX-1 by CHB patients who survived NPC was similar to that of CHB patients without NPC. This raises the question as to whether LOX-1 expression may be associated with the suppression of T-cell responses.

In summary, dsDNA viruses show a correlation between viral infection and LOX-1 upregulation. However, it is still not known whether atherosclerosis and LOX-1 upregulation are direct effects of the viral infection or if they result as a side effect of the immune response. Furthermore, a potential inhibitory effect on T-cell responses has been observed. The signaling pathways leading to LOX-1 upregulation during these infections are still unclear and need further investigation.

Fungi

In fungal infections, LOX-1 has been investigated in the context of A. fumigatus keratitis. It has yet to be established whether LOX-1 can also interact with other fungi.

A. fumigatus

A. fumigatus is the most common pathogen causing fungal keratitis, an infectious disease affecting the cornea. He et al. [119] demonstrated that LOX-1 is significantly upregulated in mice with fungal keratitis and seems to be linked to the expression of TNF, CXCL1, IL-6, IL-10, and MMP-9. Inhibition of LOX-1 expression resulted in reduced expression of CXCL1, IL-6, and IL-10 in macrophages and decreased expression of TNF, CXCL1, MMP-9, IL-6, and IL-10 in neutrophils. These findings suggest that LOX-1 may regulate the expression of both anti-inflammatory and proinflammatory cytokines in the cornea of infected mice. Moreover, inhibiting LOX-1 appears to stabilize the immune response during fungal keratitis.

Furthermore, in macrophages and neutrophils, it was shown that HMGB1 upregulates LOX-1 through the DNA-binding domain BoxB [111]. Another inflammatory factor involved in the host immune response is activating transcription factor 4 (ATF4), which was shown to be dependent on LOX-1, ERK1/2, TLR4, and the JNK pathway in fungal keratitis [141]. It was also observed that inhibiting LOX-1 leads to a decrease in protein levels of adhesion factors such as VCAM-1, ICAM-1, P-selectin, E-selectin, and LFA-1. Additionally, LOX-1 inhibition in mice significantly reduces neutrophilic infiltration [142].

These regulatory effects of LOX-1 in A. fumigatus keratitis suggest that LOX-1 might be involved in fungal adhesion, neutrophil infiltration, and upregulation of the inflammatory response. Further investigation is required to understand the specific ways in which LOX-1 directly interacts with the fungus.

Due to the importance of LOX-1-mediated pathways in different infectious diseases, the inhibition of LOX-1 expression or binding could provide new potential treatment strategies. Currently, numerous different natural and synthetic compounds are known to inhibit LOX-1 receptor function.

Natural Inhibitors of LOX-1

A diverse range of natural compounds have been identified to inhibit LOX-1 with different mechanisms [52]. One group of natural modulators are unsaturated fatty acids (FA) which indirectly inhibit LOX-1 expression. Unsaturated FAs have a downregulating effect on ER stress which regulates LOX-1 expression [143]. A second group is antioxidants, which follow two pathways to inhibit LOX-1. First, the LOX-1 signaling pathway is inhibited by the reduction of the oxLDL level. Second, antioxidants inhibit NF-κB, which is known to upregulate LOX-1 [52]. Furthermore, some commonly known compounds are capable of downregulating LOX-1 expression. Examples include cumin and bergamot essential oils, the latter of which also acts as an antioxidant [27, 144, 145]. Other downregulating compounds are berberine, tetramethylpyrazine, pterostilbene, selaginellin, 6-shagol, ellagic acid, and diphenyleneiodonium (NADPH inhibitors) [27, 146‒151]. Recent research has shown that gallic acid has anti-inflammatory effects and inhibits LOX-1 production [152]. Hydroxymethylglutaryl-CoA-reductase (HMG-CoA-reductase) inhibitors, namely, statins, reduce cardiovascular mortality by decreasing cholesterol as well as by non-lipid-related actions [153].

Wang et al. [154] recently showed that thymol, which can be found in essential oils, inhibits LOX-1/IL-1β signaling, and the growth of A. fumigatus and could therefore be a useful treatment for fungal keratitis. However, thymol exhibits cytotoxic effects on HCECs, which is why the concentration must be considered carefully. A concentration of 50 μg/mL did not show obvious side effects in mice [154]. Another antifungal substance is β-ionone, which also suppresses the inflammatory response to an A. fumigatus infection through suppressing LOX-1 and JNK/p38 MAPK [155].

Synthetic LOX-1 Inhibitors

Several LOX-inhibiting therapies have already been developed, specifically for the treatment of atherosclerosis [27]. As a direct inhibitor of LOX-1, Falconi et al. [156] generated the modified oxidized phospholipid PLAzPC. This phospholipid directly inhibits the binding of LOX-1 to oxLDL by disrupting the hydrophobic component of the oxLDL recognition domain. This enables the charged groups of the L-lysine backbone to interact with the solvent and the hydrophobic tunnel of LOX-1, resulting in the inhibition of oxLDL binding [156]. Another compound with a direct influence on LOX-1 is BI-0115, a small-molecule inhibitor. Schnapp et al. [157] demonstrated that two BI-0115 molecules bring together the heads of two LOX-1 dimers, leading to the inhibition of its normal function. While oxLDL and angiotensin II stimulate the maturation of human monocyte-derived DCs, losartan, an angiotensin II blocker, can reduce oxLDL-dependent LOX-1 expression and thus also the maturation of human monocyte-derived DCs [158].

Furthermore, there are drugs with indirect effects on LOX-1 expression. For example, aspirin is commonly used for cardiovascular disease treatment and also exhibits downregulating effects on LOX-1 expression. The salicylate component of aspirin inhibits superoxide anion generation, while p38MAPK serves as a target for aspirin action [68]. Antihypertensive agents like calcium channel blockers or AT1R blockers (ARBs) are also employed in acute cardiovascular events. The calcium channel blockers amlodipine inhibits LOX-1 overexpression by reducing the associated NADPH oxidase and NF-κB activity [52, 159]. Anti-inflammatory drugs, such as NF-κB inhibitors, can also induce LOX-1 inhibition because NF-κB regulates the LOX-1 expression by binding to its promoter [52, 160]. Another group of LOX-1 inhibitors are HMG-CoA reductase inhibitors, commonly known as statins. While statins, like lovastatin, have downregulating effects on cholesterol, they also reduce LOX-1 expression. However, whether these two effects are related remains unknown [52, 161, 162]. Another substance with LOX-1-downregulating effects is niclosamide. It is commonly used as a treatment against tapeworms and also alters plaque composition to a less necrotic phenotype while downregulating LOX-1 expression [163].

LOX-1 plays a fundamental role in inflammatory conditions, notably atherosclerosis and other cardiovascular diseases. Moreover, recent scientific findings are increasingly indicating the involvement of LOX-1 in infectious processes. LOX-1 seems to respond to various bacterial, viral, and fungal infections within different tissues and cell types. Despite some identified interactions, the precise signaling routes of LOX-1 and its specific engagement with pathogens require further exploration. However, the scientific model for the study of LOX-1 should be chosen with care as structural differences between different species, particularly between rodents and humans, have been documented. Whether these differences influence the functions and interactions of LOX-1, however, still needs to be examined.

We want to express our gratitude to Dr. Lavinia Neubert (Hannover Medical School) for reviewing and giving important recommendations for this report. Sarah Truthe was supported by the Hannover Biomedical Research School (HBRS) and the Center for Infection Biology (ZIB).

The authors have no conflicts of interest to declare.

This work was supported by the German Research Foundation (Collaborative Research Center/Transregio 124 – FungiNet – Pathogenic fungi and their human host: Networks of Interaction, DFG project number 210879364) to H.S. This work is further funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2155 – project number 390874280.

S.T., T.E.K., and H.S. reviewed publications and designed the review. S.T., T.E.K., S.S., and W.B. created the figures and did the structural analyses. S.T. wrote the manuscript. S.T., T.E.K., D.J., and H.S. contributed to the study design, interpretation of the research articles, editing of the manuscript, and critical revision of the manuscript. All authors read and approved the final manuscript.

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