Autism spectrum disorder (ASD) is a highly prevalent developmental disorder characterized by deficits in communication and social interaction and in stereotyped or repetitive behaviors. Besides the classical behavioral dyad, several comorbidities are frequently present in patients with ASD, such as anxiety, epilepsy, sleep disturbances, and gastrointestinal tract dysfunction. Although the etiology of ASD remains unclear, there is supporting evidence for the involvement of both genetic and environmental factors. Valproic acid (VPA) is an anticonvulsant and mood stabilizer that, when used during the gestational period, increases the risk of ASD in the offspring. The animal model of autism induced by prenatal exposure to VPA demonstrates important structural and behavioral features that can be observed in individuals with autism; it is thus an excellent tool for testing new drug targets and developing novel behavioral and drug therapies. In addition, immunological alterations during pregnancy could affect the developing embryo because immune molecules can pass through the placental barrier. In fact, exposure to pathogens during the pregnancy is a known risk factor for ASD, and maternal immune activation can lead to autistic-like features in animals. Interestingly, neuroimmune alterations are common in both autistic individuals and in animal models of ASD. We summarize here the important alterations in inflammatory markers, such as cytokines and chemokines, in patients with ASD and in the VPA animal model.

Since the first descriptions in the early 1940s, new data has been shared to the scientific community about autism spectrum disorder (ASD) [1]. Currently, ASD is diagnosed by changes in 2 behavioral domains: (a) communication and social interaction impairments in multiple contexts, including deficits in social reciprocity and nonverbal communication used for social interaction and in skills to initiate, maintain, and understand relationships; and (b) Repetitive behaviors, and restricted and stereotyped activities [2].

There is no clinical marker or quantitative examination in peripheral tissues that can be used for an early diagnosis of this disorder [3]. Even though there are many well-accepted surveys for behavioral diagnosis, ASD is a highly complex and heterogeneous disorder, presenting distinct manifestations, with no two individuals sharing the same set of symptoms [4, 5]. The large heterogeneity of the symptoms could potentially be explained by individual differences, for example in the immune system. Alterations in cytokine levels are common in autistic individuals, with a frequent observation of elevated levels of proinflammatory cytokines [6, 7].

Genome-wide association studies (GWAS) have already described interesting relations between immune system disruptions and neurological disorders like autism and schizophrenia [8]. Specifically, in ASD, an interesting example is the dysregulated genes reported, i.e., IL-1β and IL-12, both involved in cytokine-cytokine receptor interaction [9]. One study relating ASD and neuroimmune genetic disruption shows an alteration in glutamate receptor metabotropic 5 (GRM5) single-nucleotide polymorphisms (SNPs) [10]. This is not exactly a neuroimmunological alteration, but this gene is highly expressed in many neuronal regions implicated in ASD, besides acting on synaptic plasticity, modulating innate immunity, and microglia activation. When GRM5-positive allosteric modulation occurs, several negative behaviors described in ASD are rescued, including stereotypy [10]. Evidence of an intersection of gene interactions and ASD diagnosis demonstrates the importance of the genetic contribution to the neuroimmunological imbalance in ASD.

According to the most recent epidemiological survey conducted in the USA, the current incidence of ASD is 1: 68 [11]. Although the etiology of ASD remains unknown, it is hypothesized that the onset of this disorder depends on the interplay between genetic and environmental factors. Epidemiological observations suggest that exposure to teratogens, especially in the first trimester of pregnancy, could be closely related to ASD development. An important example is the prenatal exposure to valproic acid (VPA) [12, 13].

The compound VPA is a drug widely used as an anticonvulsant and mood stabilizer in the treatment of epilepsy and bipolar disorder [13, 14]. Although VPA is well tolerated and safe in adults, there is evidence of its teratogenicity [14]. Clinical studies over the years have shown that intrauterine exposure to VPA is associated with birth defects, cognitive impairments, and an increased risk of autism [13]. In recent years, animal studies have investigated the anatomical, behavioral, molecular, immunological, and physiological outcomes related to exposure to VPA [13].

Epidemiological observations demonstrate a strong correlation between prenatal exposure to VPA and ASD [15-18]. Based on these observations, an animal model for the study of autism prenatally induced by VPA was established [19-21]. Behavioral studies show that exposure to VPA in rats and mice leads to several autistic-like behaviors in male offspring, including social behavior deficits, increased repetitive behaviors, and communication deficits similar to those found in ASD subjects [19-23]. This points to the animal model being translational, as the diagnosis of ASD is given through behavioral evaluation.

Since the current diagnostic criteria for ASD are exclusively clinical and are the result of behavioral analyses, the study of ASD in humans prior to the onset of symptoms becomes a very challenging task. Animal models provide the opportunity for analyzing the developmental changes that can trigger ASD-like features [24, 25]. They provide the possibility to study and manipulate biological pathways for understanding, and even preventing or reversing, the appearance of the morphological, functional, and behavioral alterations found in ASD. Studies on animals can also reveal some new important factors involved in the etiology of this disorder.

Histone-Deacetylases Inhibitors and Neuroimmune Alterations

Autism and many other psychiatric disorders, like schizophrenia, bipolar disorder, and major depression, present not only susceptibility to environmental risk factors, but also a high genetic influence [26, 27]. In the last years, there is growing evidence indicating that epigenetic alterations may have an important role in several psychiatric disorders.

Epigenetic regulation includes long-term changes, like DNA methylation, and short-term changes, like modifications in the histone proteins associated with DNA [28]. Histones are small basic proteins that act as spools around which DNA winds, regulating the packaging of DNA and allowing or inhibiting gene expression. When the histone is acetylated by histone acetyltransferases, this local alteration leads to chromatin decondensation, promoting gene expression by the activation of the transcription machinery. On the other hand, histone deacetylation, mediated by histone deacetylases (HDACs), results in the inhibition of transcription, promoting a controlled gene expression [28, 29].

Substantial epigenetic alterations have been found in the regulatory regions of many candidate genes for ASD, such as the GABAergic genes, GAD67, Reelin, oxytocin receptor, and BDNF, showing that the epigenetic component in ASD has been widely studied [26]. Histone posttranslational modifications, like acetylation and methylation, play a key role in the regulation of gene expression [30]. These characteristics are crucial for important biological processes like the actions of immune system, in which HDACs modulate the gene expression of toll-like receptors (TLRs) and interferon (IFN) signaling pathways [31].

The HDAC inhibitor drugs play an important role in the immune context. Studies show increased transcription of the major histocompatibility complex (MHC) class II, located in the tumor cell surface in mouse and humans [32], indicating an interesting effect on several immune cells. It leads to less viability of T CD4 cells and decreases the production of proinflammatory cytokines, making the T CD8 cells increase the secretion of proinflammatory cytokines, modulating the activity of natural killer (NK) cells and regulatory T cells [33].

Hence, several drugs used as antidepressants and mood stabilizer are characterized as HDAC inhibitors. Valproate, a well-known HDAC inhibitor drug, induces important delays in neuronal maturation [34], already described in ASD [35]. Moreover, VPA prenatal exposure alters the postnatal histone 3 (H3) acetylation levels in the cerebellum [36], stimulates glial cell proliferation in the developing rat brain [37], and also induces changes in acetylation levels in the astrocytes of the hippocampus and cortex in cell culture more than other antidepressants and mood stabilizers do [38]. These unique effects of VPA, especially in comparison to similar HDAC inhibitor drugs, indicate that the VPA molecule might have exclusive properties which are still unclear, although some evidence indicates a possible VPA binding in the catalytic center of HDACs [39]. Those epigenetics alterations occur before the well-described neuroimmune alterations, and may therefore be involved in the immune disturbances [36]. These data highlight the role of VPA and HDAC inhibitors as epigenetic modulators, which could be underpinning the immunological alterations as well as the neurological outcomes in psychiatric disorders.

For a long time, the immune system and the central nervous system (CNS) were considered compartments that operate separately and independently. However, recent studies demonstrate an active communication between these two systems, whereby they modulate each other “bi-directly” with neurotransmitters and neuromodulators in the periphery. In addition, in a landmark study, lymphatic vessels were discovered in the CNS, putting in check the current view of the brain as an “immune privileged site” and raising new possibilities for the crosstalk between the brain and the immune system [40]. Anatomically, the CNS is bathed by the cerebrospinal fluid (CSF), and surrounded by the meninges which contain lymphatic and blood vessels [41]. The brain parenchyma is separated from the circulating blood by a blood-brain barrier (BBB) which prevents the entry of pathogens, circulating immune cells, and other substances from the blood.

The BBB is defined as a semipermeable membrane that separates the circulating blood from the brain and extracellular fluid in the CNS [42]. CNS blood vessels interact with different peripheral and brain-resident immune cell populations, like perivascular macrophages and microglial cells, respectively. The BBB is formed by the concerted action of endothelial and glial cells. During development, at embryonic day 10 (E10), initial clues for angiogenesis lead to the early properties of BBB in the CNS by activation of the Wnt/β-catenin canonical pathway [43-45]. There is no consensus about exactly when the BBB is fully formed [46]. Nevertheless, at E15, pericytes, which play a crucial role in BBB formation and maintenance, begin to interact intimately with endothelial cells (EC) in the capillary walls [47]. In postnatal life, EC of brain capillaries are covered up by mature pericytes, sharing their basement membrane with the endothelium [48]. Moreover, the astrocytes project cellular terminations called “end feet” toward the capillaries, providing the outer layer of the BBB. Pericytes and astrocytes also secrete proteins involved in extracellular matrix formation and deposition of the basement membrane [48, 49].

The presence of this limiting barrier allows the CNS to control and fine-tune the flow of a variety of molecules from the periphery, regulating its permeability to seek homeostasis. In CNS physiology, there are extensive vessels where monocytes, granulocytes, and dendritic cells (DC) circulate [50]. In addition, the brain parenchyma is populated with microglia, resident cells from the immune lineage that play a crucial role in brain surveillance and response against multiple types of damage. Studies on rodents show that, during neurodevelopment, specific monocytes emerge at E7 and infiltrate the CNS at E9.5 as premacrophages, expressing the chemotactic factor CX3C chemokine-receptor 1 (CRXCR1) [50]. The presence of cytokines like interleukin (IL)-1β and tumor growth factor (TGF)-β allows the differentiation of premacrophages in early microglia at E14.5, which then generate mature microglia at P14. In fact, TGF-β seems to be crucial for microglial specification in the CNS [51, 52].

Microglial cells are capable of interacting with almost all cell types in the CNS, modulating cell maturation during development and promoting tissue repair and homeostasis. Moreover, in postnatal life, microglia play a crucial role in sensing perturbations in the encephalic environment, actively responding to even minor pathological changes in the CNS [53, 54] by altering their shape and gene expression profile. The term “microglial activation” has been considered as a shift from a “resting” to an “activated” state when a disturbance in tissue homeostasis is detected or upon experimental stimulation. However, this term implies the understanding of an “inactivated” phenotype when the brain tissue is not facing any changes in homeostasis. In fact, microglial cells are never inactive and show highly dynamic surveillance functions in the CNS [50, 55, 56]. Many authors suggest this surveillance state of the microglial cells be renamed “surveying microglia” instead of “resting microglia” [50]. These cells can shift from their “surveying” or “resting” state to “activated” or “alerted” state when facing chances in CNS homeostasis, like infections recognized by TLRs [57], cell damage, or trauma.

Recent studies have demonstrated that lipopolysaccharide (LPS) exposure downregulates the transcription factor Sal-like protein 1 (SALL1) and promotes several alterations in microglial identity, with a concomitant upregulation of genes associated with other resident macrophages, indicating that SALL1 might be important for the maintenance of microglial identity in response to immune challenge [50, 58]. Once activated, microglial cells can commit to different “reactive” phenotypes which have a large functional and molecular diversity. These changes in microglia profile are correlated with the type of challenge faced by the CNS. They can shift to a proinflammatory state, also called the “M1 phenotype” [59], presenting highly phagocytic and neurotoxic activities and releasing proinflammatory chemokines and cytokines in response to an immune challenge, such as a microorganism invasion [60], or the presence of proinflammatory signals [61-63]. Once the immune stimulator is controlled, microglial cells are able to shift to a more neuroprotective profile called the “M2 phenotype” which involves anti-inflammatory responses [59, 64]. Nonetheless, the activated proinflammatory profile can progress in pathological conditions. Although the immune challenge and the brain environment are responsible for the early microglial responses, signals from CNS resident and infiltrating immune cells can shape the reactive profiles of microglial cells and play an important role in many brain diseases [65-69]. All these stimuli could direct the fate of the microglia to alternative states, including microglial cell death, but information remains scarce as to the course of microglial activation, their reversibility to the surveying state [70], or the preservation of the molecular memory of previous stimuli. Moreover, cells that infiltrate from the blood and differentiate into microglia could also return to the periphery [65, 71].

There is a low basal entry of immune cells from the blood periphery into the CNS under normal conditions. Studies have shown that, although microglial cells play a major role in brain surveillance, perivascular macrophages represent a crucial immune regulator and sensor of perturbations in the CNS and periphery. These cells are derived from the bone marrow and are intimately associated with the bloodstream since they reside between EC and astrocyte end feet [72-74]. This privileged location of the perivascular macrophages allows them to simultaneously monitor the blood and the brain interstitial fluid, providing a fine control of brain homeostasis and BBB integrity [72, 75].

Macrophages are to be found at different locations, and they can perform specific roles in these microenvironments. In addition to the perivascular space, they are located within the choroid plexus and meningeal space. In the choroid plexus, which is considered the major site of CNS immune surveillance, there are tissue-resident macrophages called epiplexus cells residing alongside the fourth ventricle with DC, monocytes, and mast cells [76, 77]. Referred to by many authors as the “immune regulatory gate,” the choroid plexus is able to induce specific immune responses and allows cell migration between the blood and CSF [78, 79].

The meningeal macrophages are positioned in the subdural meninges and act as sentinel cells for the damage and infection of brain tissue, by surveying the CSF and the extracellular lumen of meningeal blood vessels [80, 81]. Thus, macrophages play critical roles in CNS surveillance, homeostasis, and disease.

Nonetheless, there is a variety of other immune cell types in the brain environment. In the physiological condition, studies have observed the presence of monocytes in meningeal spaces, although more evidence is still needed [82]. Granulocytes (i.e., neutrophils, mast cells, eosinophils, and basophils) can be found in meningeal spaces with mast cells also present in brain parenchyma [72, 83]. These cells are highly phagocytic and play important roles in response to brain infections and tissue damage [72, 84, 85]. DC, the main antigen-presenting cells in the periphery, can also be found in the CNS. They are located in the choroid plexus, meningeal space, and are especially abundant in lymphatic vessels in meninges [86-88]. The presence around these vessels suggests important roles for DC in inflammatory diseases and brain infections [40].

Under inflammatory conditions, there is extensive infiltration of immune cells into the CNS. The barriers that regulate cellular entry are the BBB within the CNS parenchyma and the blood-CSF barrier within the choroid plexus [89]. When brain homeostasis is compromised, immune cells can infiltrate from the periphery to the brain parenchyma due to the elevation in BBB permeability. This is generally observed and investigated in the context of a pathological CNS inflammatory response [90-92].

Under pathological conditions, microglia activation can lead to BBB disruption, allowing a substantial infiltration and amplifying the inflammatory response [93, 94]. One of the key mediators in these processes is the release of cytokines and chemokines by the periphery and brain-resident immune cells. This novel view of the immune system as an active player in brain function is modifying our current view of neuropsychiatric disorders. Immune alterations are now seen as central to the pathophysiology of many brain diseases, and a greater understanding of this neuroimmune axis will result in new therapies and diagnostic tools.

In the last decade, the immune system has caught the attention of neuroscientists for the interplay between neurons and immune mediators, not only in disease, but also in the homeostasis of the brain. In the past, the CNS was called “an immune-privileged region” with the BBB controlling the crosstalk between the brain and the periphery. However, recent findings demonstrated that this privilege is not related to the absence of immune modulation in brain activity and homeostasis, but rather a time-dependent specific modulation in many regions during brain development [95].

Immune cells and immune molecules, such as cytokines and chemokines, can modulate cognitive, emotional, and behavioral processes, triggering different responses in neuronal and glial cells [96]. Cytokines are small signaling molecules that act as mediators of communication between immune cells. Their roles include the stimulation and regulation of cell development, maturation, and the response to immune challenges [97, 98]. Chemokines can be characterized as a vast group of 8- to 10-kDa molecules from the superfamily of cytokines, that induce the chemotaxis of immune cells. Once bound in their receptor, the complex chemokine-receptor can activate signaling cascades that induce immune cell-trafficking to the target area. This complex is also important as a molecular signal in the crosstalk among neuronal and glial cells and immune resident cells in the nervous system (e.g., microglia) [99, 100]. Since chemokines have the capacity to target different types of receptor, they can modulate different cell processes, including cell adhesion and proliferation, phagocytosis, apoptosis, angiogenesis, cytokine secretion, and T cell activation [101].

Lymphocytes are cells capable of recognizing any foreign antigens displayed by antigen-presenting cells, thereby constituting the main cells of adaptive immunity [102]. Lymphocytes respond by proliferating and differentiating in effector cells, whose function is the elimination of the pathogen and the creation of an immunological memory [103]. When naïve CD4+ T cells encounter specific antigens, they can differentiate into a range of effector subgroups. Several transcription factors are individually required for T cell differentiation, generating a specific lineage that expresses characteristic cytokines. So, once the transcription factors are activated, they promote the differentiation of naïve T cells, which then differentiate, according to specific immunological responses, into T helper (Th)1, Th2, and Th17 cells. In the presence of IFN-γ and IL-12, signal transducer and activator of transcription (STAT)1 and STAT4 signal the expression of the transcription factor T box expressed in T cells (T-bet), promoting a Th1 response. On the other hand, Th2 cell commitment occurs when IL-4 and STAT6 increase the expression of GATA-binding protein 3 (GATA3) transcription factor. The presence of TGF-β associated with IL-6 signaling via STAT3, generates the expression of a retinoid-related orphan receptor γ isoform (RORγt) transcription factor, resulting in the differentiation of Th17 cells. TGF-β associated with IL-2 signaling via STAT5, is known to generate, at least in vitro, inducible regulatory T cells which express Foxp3 transcription factor (Fig. 1) [104].

Fig. 1.

Th1, Th2, and Th17 commitment lineages from naïve CD4+ T cells. The main functions of each immune response and the signature cytokine are highlighted in the boxes. APC, antigen-presenting cell; NK, natural killer cell; T-bet, T box expressed in T cells; GATA3, GATA-binding protein 3; RORγt, a retinoid-related orphan receptor γ isoform; IL, interleukin; IFN, interferon; TGF, transforming growth factor.

Fig. 1.

Th1, Th2, and Th17 commitment lineages from naïve CD4+ T cells. The main functions of each immune response and the signature cytokine are highlighted in the boxes. APC, antigen-presenting cell; NK, natural killer cell; T-bet, T box expressed in T cells; GATA3, GATA-binding protein 3; RORγt, a retinoid-related orphan receptor γ isoform; IL, interleukin; IFN, interferon; TGF, transforming growth factor.

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The modulation of cytokine levels can significantly alter brain physiology and also behavior. Recent studies highlight a link between immune dysfunction and behavioral impairments [105]. For example, the relation between IL-6 and several altered behaviors has already been established in the literature [106-108]. Signs of neuroinflammation and altered inflammatory responses are seen in ASD subjects throughout life [109]. Therefore, some authors hypothesize that the neuroimmune disturbances could be causal for ASD [110]. Below, we provide the details of the main neuroimmunological findings (Tables 1, 2) in ASD subjects and the VPA animal model of autism.

Table 1.

Main cytokines with altered levels in autism subjects

Main cytokines with altered levels in autism subjects
Main cytokines with altered levels in autism subjects
Table 2.

Main cytokines with altered levels in the VPA animal model of autism

Main cytokines with altered levels in the VPA animal model of autism
Main cytokines with altered levels in the VPA animal model of autism

Interleukin 1β

IL-1β is a cytokine produced by fibroblasts, monocytes, tissue macrophages, DC, B lymphocytes, epithelial cells, and NK cells [111], that promotes inflammation by indirectly stimulating lymphocyte function and activating macrophages [112, 113]. IL-1β has the ability to increase the expression of adhesion molecules such as VCAM-1 and ICAM-1, supporting the infiltration of inflammatory cells from the circulation into the tissue, and resulting in chronic IL-1-induced inflammation [112, 113]. IL-1β stimulates the expression of inflammatory mediators and induces a Th17 response. It also plays an important role as a mediator of the anti-inflammatory response [112, 113].

Both elevations and reductions in IL-1β levels have been reported in ASD subjects. Increased levels of IL-1β were found in plasma [114, 115], serum [116, 117], and peripheral blood mononuclear cells (PBMC) [118-120]; decreased levels were described in neonatal dried-blood samples (n-DBSS) [121]. In the VPA animal model, IL-1β was increased in the hippocampus [122, 123], an LPS-exposed hippocampus [109], and a whole-brain homogenate [124]. Increased levels of this cytokine are associated with increased stereotypy [120], one of the main characteristics of ASD.

Interleukin 2

IL-2 plays an important role, controlling the survival of immature and mature T cells [125]. It is mainly secreted by CD8+ and CD4+ T cells after recognition of the antigen and costimulators [111]. IL-2 is the most important cytokine for promoting the clonal expansion of antigen-activated T cells [126]. The only report concerning ASD was of a reduction of IL-2 levels in n-DBSS [121].

Interleukin 4

IL-4 is the main cytokine of Th2 response and is primarily produced by T cells and mast cells. IL-4 promotes the proliferation of B cells and cytotoxic T cells and stimulates IgG and IgE production [97]. It stimulates leukocyte recruitment and promotes the expression of adhesion molecules [127]. Increased levels of this cytokine have been associated with greater impairments in nonverbal communication [120]. In ASD subjects, reduced levels of IL-4 in n-DBSS [121] and elevated levels in amniotic fluid [128] have been reported.

Interleukin 5

IL-5 is a cytokine produced by T cells that acts as an activator of eosinophils [129]. IL-5 promotes eosinophil proliferation and maturation, stimulating IgA and IgM production [97]. In ASD patients, a decrease in IL-5 in n-DBSS [121] and an increase in plasma samples [115] have been described.

Interleukin 6

The main sources of IL-6 are Th cells, macrophages, and fibroblasts. IL-6 targets activated B cells and plasma cells, promoting the differentiation into plasma cells and the production of IgG [97]. IL-6 is also involved in the induction of a Th17 response and it has a dual profile, i.e., pro- and anti-inflammatory [112, 113]. Studies have demonstrated the essential involvement of IL-6 in triggering core symptoms related to the proinflammatory response in the autistic model of maternal immune activation (MIA) [130].

Increased levels of IL-6 are associated with increased stereotypy in ASD [120], impaired cognitive abilities, abnormal anxiety, and decreased social interactions [107]. We reviewed the main findings about IL-6 levels in ASD: IL-6 is elevated in the brain tissue (cerebellum, frontal cortex, and anterior cingulate gyrus) [7, 131, 132], serum, and PBMC [116-120], but is reduced in plasma and n-DBSS [114, 121]. In the VPA animal model of autism, higher levels of IL-6 were reported in the hippocampus [123], the hippocampus and spleen after LPS challenge [109], and a whole-brain homogenate [124].

Interleukin 8

IL-8 is a chemoattractant cytokine produced mainly by macrophages that specifically targets neutrophils, promoting their activation [133]. So its major functions result from its chemotactic and proinflammatory activities [97]. Elevated levels of this cytokine are associated with increased hyperactivity, stereotypy, and lethargy [120]. Higher levels of IL-8 have been observed in the frontal cortex [132], plasma [115], CSF [134], PBMC [120], and n-DBSS [121] of ASD subjects.

Interleukin 10

This cytokine can be produced by several types of cells including DCs, macrophages, mast cells, NK cells, eosinophils, neutrophils, and B cells [135]. It is able to regulate the growth and/or differentiation of B cells, NK cells, cytotoxic T cells, Th cells, mast cells, granulocytes, DC, keratinocytes, and EC, exerting a primarily anti-inflammatory activity [97, 135]. IL-10 is important to fine-tune the immune response against invading pathogens, maintaining the homeostatic state [135]. In ASD patients, increased levels were found in the anterior cingulate gyrus and the amniotic fluid [128, 134], and decreased levels were found in PBMCs [96].

Interleukin 12

IL-12 is produced by T cells and acts on naïve T cells and NK cells, activating them [97] and also inducing IFN-γ production, which is critical for the induction of Th1 cells [136]. Plasma, PBMC, and serum of ASD subjects show higher levels of IL-12 [115, 117, 120] whereas n-DBSS show lower levels [121]. Increased IL-12 levels are associated with increased stereotypy and lethargy in ASD patients [120].

Interleukin 13

Similar to IL-4, IL-13 is involved in type 2 immunity and is produced by T cells. However, basophils, eosinophils, and NK cells can also produce IL-13 [137]. The only report concerning autistic patients showed increased plasma levels of IL-13 [115].

Interleukin 17

IL-17 plays an important role in the immunity against intra- and extracellular pathogens [138]. IL-17-producing cells, including NK cells and innate lymphoid cells, play crucial roles in inflammation-associated disease, such as infection, autoimmunity, and tumors [139]. The effector role of IL-17a at the onset of MIA-induced behavioral abnormalities in offspring has also been described, showing the important crosstalk between the neuroinflammatory state and behavioral manifestations [140]. Increase levels of IL-17 have been reported in the plasma and serum [115, 141] of patients with ASD.

Interleukin 23

Considered a proinflammatory cytokine essential for the differentiation of Th17 lymphocytes [142], IL-23 is produced by macrophages, DC, keratinocytes, and other antigen-presenting cells after the recognition of microorganisms [143]. IL-23 is critically involved in autoimmune disease responses [144]. In autistic patients, elevated IL-23 levels in serum samples have been reported [117].

Tumor Necrosis Factor α

TNF-α is an endotoxin-induced serum factor promoting phagocyte cell activation [97], whose main targets and producers are macrophages. TNF-α is found at higher levels both in ASD patients (frontal cortex [132], PBMC [96, 118, 119, 145], serum [117], and amniotic fluid [128]) and in the VPA animal model of autism (in the hippocampus and spleen responding to LPS [109] and in whole-brain tissue [124]).

Interferon γ

IFN-γ plays an important role in the host defense against intracellular pathogens. It is produced by NK T cells, CD8+ T cells, and CD4+ T cells, and its functions include supporting Th1 differentiation [146], macrophage activation, and increasing neutrophil and monocyte function [97]. Patients with ASD have increased levels of IFN-γ in the frontal cortex [132], plasma [147], CSF [134], and PBMC [96], and reduced levels in n-DBSS [121].

Tumor Growth Factor β

TGF-β is primarily secreted by T cells and B cells, and acts in activated T and B cells. The major function of this cytokine is to inhibit hematopoiesis and T and B cell proliferation [97]. Higher levels of TGF-β1 were reported in the anterior cingulate gyrus and CSF [134] of ASD subjects.

Monocyte Chemoattractant Protein 1

Monocyte chemoattractant protein 1 (MCP-1) or C-C chemokine ligand 2 (CCL2) signals to cells that contain the specific CCR2 receptor, stimulating their migration to sites where CCL2 is produced, and thereby facilitating the amplification of neuroinflammation [148]. Higher levels of MCP-1 have been observed in the plasma [149], CSF [134], and amniotic fluid [128] of autistic subjects. Increased levels in the plasma are associated with greater impairments in visual reception, fine motor skills, and expressive language [149].

Granulocyte-Macrophage Colony-Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is produced by T cells, macrophages, and fibroblasts, and targets stem cells. Its major function is to stimulate the production of granulocytes, monocytes, and eosinophils [97]. Diminished levels of GM-CSF have been described in the n-DBSS of pediatric ASD subjects [121].

Granulocyte Colony-Stimulating Factor

The main sources of granulocyte colony-stimulating factor (G-CSF) are fibroblasts and EC, and its targets are stem cells in the bone marrow. G-CSF has a hematopoietic function and stimulates granulocyte production [97]. Higher levels of this cytokine have been observed in the plasma of autistic patients [114].

Epidermal Growth Factor

Epidermal growth factor (EGF) is a small chemoattractant peptide, produced by activated T cells, that is involved in wound-healing by attracting fibroblasts and epithelial cells [114]. Higher levels of this chemokine have been reported in plasma samples from autistic patients [114].

RANTES

Regulated on activation, normal T cell expressed and secreted (RANTES) chemokine or CCL5 is involved in immune cell transport to the inflammation site, promoting polarization towards a Th1 response [150]. Higher levels are associated with the increased severity of lethargy, stereotypy, and hyperactivity [149] in ASD patients.

Eotaxin

The CC chemokine eotaxin/CCL11 is known to bind to the receptor CCR3 on eosinophils and Th2-type lymphocytes [151]. Increased levels of eotaxin are associated with the increased severity of lethargy, stereotypy, and hyperactivity in ASD subjects [149].

There is a high prevalence and growing incidence of ASD over the last few years. This has driven investments into public health and mobilized researchers and health professionals worldwide. There has been significant progress in ASD research since the disorder was first described, but, to date, its etiology remains unclear. An interesting hypothesis is that dysregulation of neuroimmune communication is involved in the onset of ASD. In this review, we summarized the main neuroimmune alterations found in both ASD subjects and the VPA animal model of autism. Notably, several changes in the VPA model indeed reflect the alterations found to occur in ASD patients (Fig. 2). Animal models that present evidence and construct validity, such as the VPA model, can be an effective tool for the investigation of pathways and tissue alterations involved in the pathogenesis of ASD.

Fig. 2.

Main results of cytokines altered in both ASD subjects and the VPA animal model. At the interface of the columns and rows are the findings shared by human subjects and the animal model from different biological sources. See Table 1 for abbreviations and references.

Fig. 2.

Main results of cytokines altered in both ASD subjects and the VPA animal model. At the interface of the columns and rows are the findings shared by human subjects and the animal model from different biological sources. See Table 1 for abbreviations and references.

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This work was supported by development agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) e Instituto Nacional de Ciência e Tecnologia em Neuro-ImunoModulação (INCT-NIM). We would also like to thank online infographic maker, Mind the Graph (attribution share-alike 4.0 licensing) for the templates of schematic figures.

The authors have no conflicts of interest.

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