The immune system is embedded in a network of regulatory systems to keep homeostasis in case of an immunologic challenge. Neuroendocrine immunologic research has revealed several aspects of these interactions over the past decades, e.g., between the autonomic nervous system and the immune system. This review will focus on evidence revealing the role of the sympathetic nervous system (SNS) in chronic inflammation, like colitis, multiple sclerosis, systemic sclerosis, lupus erythematodes, and arthritis with a focus on animal models supported by human data. A theory of the contribution of the SNS in chronic inflammation will be presented that spans these disease entities. One major finding is the biphasic nature of the sympathetic contribution to inflammation, with proinflammatory effects until the point of disease outbreak and mainly anti-inflammatory influence thereafter. Since sympathetic nerve fibers are lost from sites of inflammation during inflammation, local cells and immune cells achieve the capability to endogenously produce catecholamines to fine-tune the inflammatory response independent of brain control. On a systemic level, it has been shown across models that the SNS is activated in inflammation as opposed to the parasympathetic nervous system. Permanent overactivity of the SNS contributes to many of the known disease sequelae. One goal of neuroendocrine immune research is defining new therapeutic targets. In this respect, it will be discussed that at least in arthritis, it might be beneficial to support β-adrenergic and inhibit α-adrenergic activity besides restoring autonomic balance. Overall, in the clinical setting, we now need controlled interventional studies to successfully translate the theoretical knowledge into benefits for patients.

The autonomic nervous system (ANS) mainly consists of 2 branches, the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS) with their main neurotransmitter being the catecholamine norepinephrine (NE) and acetylcholine, respectively [1]. This review mainly focuses on the SNS and its neurotransmitters since the SNS is involved in all parts of the neuroimmune circuit, including the cholinergic anti-inflammatory reflex [2, 3]. Besides the hard-wired part of the SNS, catecholamines are also provided by the adrenal gland producing adrenaline and also by many local cells and immune cells that can acquire the ability to produce catecholamines endogenously [4‒7].

The SNS and the immune system are embedded in an integral body network together with many other systems to maintain physiological functioning within certain homeostatic limits. When homeostasis in this network is challenged, the whole system reacts to restore homeostasis. This is a stress response where the stressor can be every challenge strong enough to endanger whole body homeostasis, e.g., psychological stress, injury, or infection [8‒12].

A simple example is acute infection, where an intruder like a bacterium enters the body, is sensed by the immune system and the nervous system, and a coordinated response of several body systems is initiated to clear the intruder and return to the initial state of homeostasis [13, 14]. This initial stress reaction is similar no matter if the challenge is mere psychologic stress or any other stressor like an infectious agent. The systems have been adjusted over many million years through evolution to optimize their response toward many different challenges, but in general they always react in a similar way when homeostasis is in danger. However, if there is an intrinsic malfunction in one of the systems or the stressor is chronic because it cannot be cleared easily, a new pathologic situation is reached that demands several changes throughout the body, resulting in many different adaptational processes leading to disease sequelae [8, 9, 15]. In this review, the focus will be on the role of the SNS in chronic inflammatory diseases. The discussion of this subject will lead to an understanding of some fundamental concepts of sympatho-immune interaction, which is highly dynamic, context-, and time-dependent. After reading, it will be evident, that this interaction is mostly characterized by a proinflammatory effect of sympathetic neurotransmission around the time point of immune activation and anti-inflammatory properties in the post-activation or chronic phase of inflammation, respectively.

To introduce the common reaction to a stressor in more detail, let us consider acute infection and see how different body systems react to restore homeostasis. When an infection occurs at a certain location in the body, e.g., after injury to the skin with entrance of bacteria, first, cells of the innate immune system, like dendritic cells and macrophages stationed locally in the skin will get activated and start to produce several proinflammatory cytokines like interleukin (IL)-1 and tumor necrosis factor (TNF). When these cytokines are released, they can not only be sensed by other immune cells, which mostly get activated, but they will also be sensed by nerve endings baring cytokine receptors like nociceptors or vagal afferents [16].

Stimulation of nerves by cytokines or other danger signals leads to an activation of sensory and vagal nerve fibers, resulting in a response permitting further inflammation, e.g., by release of proinflammatory mediators from nerve terminals like substance P (neurogenic inflammation) or by an activation of the whole body stress response via activation of hypothalamic areas leading to activation of the HPA axis and the SNS [15].

Historically, the SNS is seen as the fight and flight function of the ANS, preparing the body for stressors, e.g., potential injuries caused during fights. SNS activation leads to known changes like increase in heart rate, cardiac output, and blood pressure increases in catabolic state to liberate fast-acting energy resources like glucose from glycogen in the liver, increased vigilance and pupillary dilation as well as constriction of blood vessels, and increase in blood coagulability and bronchodilation. However, the SNS activation also leads to effects in the immune system to counteract an anticipated intrusion of, e.g., bacteria after potential injury. SNS activation leads to increased mobilization of lymphocytes from vessel walls and egress from lymphoid organs [17, 18], increase in lymphatic flow and antigen presentation [19] and increase in leukocyte production in the bone marrow [20].

In addition, the increased blood flow and increased mobilization of leukocytes strengthen the surveillance of tissues for potential stressors, together with the hormonal branch including the main players cortisol and adrenaline, which are released from the adrenal gland. This stress response anticipates certain changes like injuries, the necessity to run and react rapidly, or the use of more than usual muscle strength. Therefore, the stress response prepares the whole body for this stressful situation leading to a new stress homeostatic state. Overall, in this stress homeostatic state, the activity of the immune system needs to be increased and effectiveness of the immune response needs to be optimized.

With an acute stressor, the SNS contributes to this ideal state in several ways since many actions on a systemic body level (see above) and also locally in secondary lymphoid organs (SLOs), favor this state of an highly active and vigilant immune system, especially in anticipation of further challenges. As a whole body nervous system, the ANS has an important role in coordinating an integral defensive network. For this purpose, the ANS needs to be able to communicate with all relevant body systems. This is well established for several systems like the cardiovascular system but is also true for the immune system [9, 15].

To communicate with immune-relevant cells, these cells need to be able to receive and integrate signals via neurotransmitter receptors. It has been shown for all immune cells that they possess functional adrenergic receptors, although the pattern of adrenergic subtypes might differ in certain cells and be dependent on disease state and inflammatory milieu [21]. However, on the level of the receptors, there is another layer of complexity in this system since downstream signal following ligand binding to adrenergic receptors is highly dynamic and not fixed to one response pattern [22, 23]. There are several reasons for this complexity at the molecular signaling level (see online suppl. Material 1; for all online suppl. material, see https://doi.org/10.1159/000530969).

In contrast to the above described proinflammatory “fight and flight” effects of the SNS on a systemic level, there have been many reports showing a dominant anti-inflammatory effect on a cellular level, mainly via βAR, foremost β2AR, and a proinflammatory action of αARs leading to the concept that anti-inflammatory effects are mediated primarily by increases in cAMP through βARs [21]. We will discuss this concept in a critical manner further down; however, for now, we have to appreciate that the system is highly complex, dynamic, and context-dependent [9, 23] (see also online suppl. Material 1). This means that simple answers to simple questions are not always possible. Statements like the SNS acts anti-inflammatory via β2AR receptors might be true in certain circumstances but wrong in others. However, one goal of understanding neuroimmune mechanisms is to define new therapeutic targets in chronic inflammation. Therefore, animal disease models or observations in humans are important to define such targets in the context of chronic inflammation and on an integral body level.

In the following section, several in vivo findings in animal models and also in humans are discussed to work out certain common patterns of the effects of the SNS in these pathophysiological situations (see also Fig. 1a). One important feature to recognize is the disease stage at which respective investigations have been undertaken since it has been shown that there can be completely different effects of sympathetic stimuli during the immunological start of a disease (peri-induction phase), or early- and late-stage disease. For the purpose of a better overview, main outcomes, interventions, and effects observed in animal models are shown in Tables 1-4 and concluded in Figure 1a.

Fig. 1.

SNS effects in chronic inflammation models by different categories. a Graphical summary of main effect of the SNS in different models of chronic inflammation grouped by peripheral/systemic (e.g., chemical systemic sympathectomy or treatment with respective adrenoceptor active drugs), local (e.g., sympathectomy only in SLOs or at local site of inflammation), and cerebral (e.g., depletion of locus coeruleus sympathetic neurons only). Red dot means overall proinflammatory, green dot means overall anti-inflammatory, and blue dot means no effect of the SNS across available data. Left part of the table summarizes data on sympathetic effect when sympathetic intervention takes place before or at time point of disease induction (peri-induction). The right part summarizes available data for sympathetic intervention after the time point of disease induction (post-induction). N/A, no data are available for these specific conditions. EAE, experimental autoimmune encephalitis. b Switch of adrenoceptor main effects dependent on time point of disease induction. Data indicate, at least in the arthritis model, that systemic β-adrenergic effects are proinflammatory (red area) peri-induction and anti-inflammatory after disease induction (post-induction) with a transition phase (yellow lines), during which outcomes are gradually changed from mainly β-adrenergic to proinflammatory α-adrenergic effects.

Fig. 1.

SNS effects in chronic inflammation models by different categories. a Graphical summary of main effect of the SNS in different models of chronic inflammation grouped by peripheral/systemic (e.g., chemical systemic sympathectomy or treatment with respective adrenoceptor active drugs), local (e.g., sympathectomy only in SLOs or at local site of inflammation), and cerebral (e.g., depletion of locus coeruleus sympathetic neurons only). Red dot means overall proinflammatory, green dot means overall anti-inflammatory, and blue dot means no effect of the SNS across available data. Left part of the table summarizes data on sympathetic effect when sympathetic intervention takes place before or at time point of disease induction (peri-induction). The right part summarizes available data for sympathetic intervention after the time point of disease induction (post-induction). N/A, no data are available for these specific conditions. EAE, experimental autoimmune encephalitis. b Switch of adrenoceptor main effects dependent on time point of disease induction. Data indicate, at least in the arthritis model, that systemic β-adrenergic effects are proinflammatory (red area) peri-induction and anti-inflammatory after disease induction (post-induction) with a transition phase (yellow lines), during which outcomes are gradually changed from mainly β-adrenergic to proinflammatory α-adrenergic effects.

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Table 1.

Effects of the sympathetic system in experimental colitis

Table 1.

Effects of the sympathetic system in experimental colitis

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Table 2.

Effects of the sympathetic system in experimental autoimmune encephalomyelitis (EAE)

Table 2.

Effects of the sympathetic system in experimental autoimmune encephalomyelitis (EAE)

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Table 3.

Effects of the SNS in a model of lymphoproliferation

Table 3.

Effects of the SNS in a model of lymphoproliferation

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Table 4.

Effects of the sympathetic system in models of rheumatoid arthritis (RA)

Table 4.

Effects of the sympathetic system in models of rheumatoid arthritis (RA)

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Effect of SNS in Models for Human Inflammatory Bowel Diseases

There are several murine models of bowel inflammation resembling immunologic features of Crohn’s disease (CD) and colitis ulcerosa (CU). Neuroimmune investigations have been undertaken in chemically induced models like oxazolone-, trinitrobenzene sulfonic acid (TNBS)-, and dextran sulfate sodium (DSS)-induced colitis and in one study in IL-10-deficient mice that develop spontaneous disease (see Table 1). TNBS colitis differs from DSS colitis since it leads to transmural and therefore CD-like disease, whereas DSS colitis mimics the cytokine milieu of both CD and CU [58]. However, since data are scarce, a detailed discussion of differences between the two models in the context of NEI research is limited. Other models, like the gene-deficient I-kappa-B kinase gamma model and the CD4+ T-cell transfer model have not been investigated in the neuroimmune context to our knowledge. The most widely used model is the DSS-induced colitis model, which resembles immunologic features, like a similar T helper type 1(Th1)/Th2 cytokine balance, the importance of IL-17, IL-23, and TNF and the importance of innate immunity in both, CD and CU [58]. Acute DSS colitis can be induced in RAG1-deficient mice, which do not mount qualitative adaptive immune responses, arguing for lower importance of adaptive immunity in the acute phase; however, progression of disease to chronic stages needs lymphocytes [59, 60].

Evidence for the effect of the SNS on experimental colitis is shown in Table 1. Most studies were performed in female C57B/6 mice using the DSS-induced colitis model. Overall, there is a consistent pattern with a proinflammatory role of the SNS around the time point of induction (peri-induction) and an anti-inflammatory effect in the acute and chronic phase of colitis, independent of the model system used and independent of type of intervention (stress, sympathectomy, electrical sympathetic stimulation, drug treatment) (for references, see Table 1). It is surprising, however, that even when the sympathetic intervention takes place starting together with the DSS treatment, the SNS seems to already act as anti-inflammatory [24]. A proinflammatory role of the SNS can only be demonstrated when stress [61] or chemical sympathectomy is applied strictly before DSS treatment [28]. These observations speak for a fast change from proinflammatory to anti-inflammatory function as soon as inflammation occurs, which is also observed in all other discussed model systems (see Table 1 and below).

Suppression of DSS colitis also works by stimulating other nerves like upper mesenteric and sacral nerves [26, 62]. There has been a discussion about the role of the vagal nerve in controlling inflammation in general [63] and also in the gut since the PNS, primarily by suppressing inflammatory cells via the alpha-7-nicotinic acetylcholine receptor is also part of an important anti-inflammatory control loop [64]. However, detailed anatomical studies and observations using surgical procedures to selectively denervate the different autonomous branches revealed first, that the anti-inflammatory reflex mediated by the PNS requires sympathetic innervation of the spleen and that gut inflammation is controlled by sympathetic not direct parasympathetic mechanisms [2, 3, 65‒67]. The dependence of the parasympathetic or cholinergic anti-inflammatory reflex on the sympathetic splenic nerve was shown in the context of experimental endotoxemia [66] and might be a general principal; however, the exact mechanism and level of interaction between the PNS and the SNS are still a matter of debate. Since the spleen itself does not contain cholinergic fibers [68], there has to be an activation of the sympathetic splenic nerve by the PNS before entering the spleen. When activated, the splenic nerve directly interacts with immune cells via release of sympathetic neurotransmitters acting via multiple G protein-coupled receptors, like adrenoceptors on immune cells [69]. This has direct immune modulatory effects, e.g., mainly immunosuppression via β2AR-dependent signals or leads to a further release of acetylcholine from acetylcholine-positive T cells that will then modulate, mainly suppress, inflammation by activating a7nAChR on immune cells, e.g., macrophages [63].

The loss of sympathetic fibers in the gut, as shown in the DSS colitis model, and also in specimens from patients with CD, is associated with increased expression of sympathetic repellents like semaphorin 3C and might result in reduced local inflammation control [28]. However, using a DSS regimen in mice and TNBS regimen in rats, which leads to less severe colitis, even shows an increased growth of sympathetic axons, which may be mediated by the proinflammatory cytokine IL-17A [70, 71]. Integrating both results, it seems that the balance between repellents like semaphorin 3C and sympathetic growth-promoting factors like IL-17A or nerve growth factor determines local sympathetic nerve density, leading to severely inflamed tissue without sympathetic neuronal control and areas of milder inflammation where central sympathetic control mechanisms might still be intact.

The anti-inflammatory properties of the SNS in colitis are confirmed in humans by results from epidemiological studies showing an increase in the risk of relapses associated with β-blocker usage [72]. In addition, human studies also revealed that besides local regulation of inflammation by the SNS directly in the gut there might be an anti-inflammatory contribution of sympathetic neurotransmitters by increasing IL-10 production in PBMCs, a mechanism that seems to be dysfunctional in ulcerative colitis [73], but the importance of IL-10-dependent pathways in the context of neuroimmune regulation has also been observed in an arthritis model [6, 9, 49].

Experimental Autoimmune Encephalomyelitis as a Model for Multiple Sclerosis

Autoimmunity against myelin induces central neuronal damage in multiple sclerosis (MS), which is a similar disease in mice when immunizing mice against myelin leads to an autoimmune response [74]. One major difference between human MS and the experimental autoimmune encephalomyelitis (EAE) model system is the induction of disease in the periphery by immunization and the need to increase blood-brain barrier permeability. Remarkably, almost all immunization models use pertussis toxin to achieve better passage to the brain. However, pertussis toxin is a strong inhibitor of Gαi-proteins leading to an interpretation difficulty when used in neuroimmune research, since cAMP levels are artificially raised at least in the peri-induction period.

An important difference between human MS and EAE resulting from the immunization strategy is a CD4 T-cell dominance in EAE as opposed to a CD8 T-cell dominance in human disease as well as a dominant spinal cord affection in mice as opposed to the brain in human MS [74]. This is of importance in the neuroimmune context since Th2 cells, a subpopulation of CD4 T cells are an exception to the rule and do not express β2AR [75].

However, neuroimmune data in EAE are instrumental since many experiments used direct modulation of the central SNS to investigate the effects on neuronal inflammation as opposed to systemic interventions. As opposed to colitis and also arthritis (see below), the role of the central SNS in EAE seems not to be biphasic and less dependent on time point of intervention, since most studies report an anti-inflammatory net effect of the SNS in EAE independent of disease phase (Table 2). Remarkably, central sympathetic neurotransmitters ameliorate EAE in the peri-induction/early phase [31, 36], as opposed to arthritis or colitis where an aggravating effect of the SNS is evident in peri-induction/early phase of disease [28, 47, 51, 53, 54]. Therefore, the central SNS seems to act mainly anti-inflammatory in the brain, not changing its net effect during EAE disease course.

On the other hand, systemic sympathetic modulation via βARs also shows a biphasic effect in EAE, however, with an anti-inflammatory effect in peri-induction/early phase and a proinflammatory effect when intervention starts after induction of EAE [29, 30]. This result is just contrary to observations from colitis and arthritis. Of course, there remains the possibility that blocking Gαi proteins with pertussis toxin in EAE models is interfering with all these results, making interpretation difficult.

One study has been conducted without the use of pertussis toxin, utilizing a MOG-specific T-cell transfer model system. Indeed, this study shows catecholamines acting proinflammatory in peri-induction/acute phase, as would be expected for an early intervention on the systemic level; however, this study focused on effects of endogenously produced catecholamines (endogenous catecholamine production; ECP) in macrophages only, which might be different from the general effects of the SNS [32]. This study showed that ECP by immune cells plays an important role in regulating inflammation in EAE [32]. In detail, this study focused on Nr4a1, which is an inhibitor of ECP in macrophages. Augmenting macrophage ECP by depleting Nr4a1 before EAE induction resulted in aggravation of EAE induced by MOG-specific T-cell transfer [32].

Of course, as for every animal model, it is always important to see if similar observations and mechanisms play a role in human disease, since it has to remain the final goal to find new targets for treatment. Interestingly, increased tyrosine hydroxylase expression, and therefore supposedly ECP, is also found in monocytes from MS patients [32]. Also, ECP of T cells and antigen-presenting cells has been suggested by in vitro experiments to play a role in aggravating inflammation during EAE by decreasing regulatory T-cell function and increasing antigen presentation via α1AR-dependent mechanisms [76].

As an additional finding, the latter and further studies noted a difference in the response of the SNS between female and male subjects, leading to the assumption that the male SNS is more reactive in an inflammatory context leading to overall pronounced neuromodulatory effects in males [29, 76, 77]. A sexual dimorphism of the structure of the locus coeruleus as well as the bed nucleus of the stria terminalis has been described [78, 79], which could be associated with these differences and might have further implications maybe contributing to sex-differences in incidence and severity of autoimmune diseases in general.

Besides regulation of inflammation, many studies also investigated changes in local neurotransmitters, like noradrenaline (NA), by inflammation, e.g., in the EAE model [31, 80, 81]. One study suggests a biphasic pattern for catecholamine content with no change or increase in neurotransmitters in the early phase and a decrease in the later phase of EAE, again with more pronounced changes in male as compared to female rats [29]. On the contrary, peripheral intracellular NA levels are increased in PBMCs of MS patients and decreased under treatment with INF-β [82, 83]. The central reduction of NA levels might be due to damage to neurons in the locus coeruleus, a major source of NE in the brain [84]. Taken together with results presented above, a depletion of central NA reduces anti-inflammatory effects, possibly promoting disease together with peripheral production of catecholamines.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease. In animal research, and also in humans, it has been shown that the disease is heterogeneous, in part induced by a certain genetic background and/or environmental factors [85]. Many studies and also clinical experience have shown several important factors that drive disease, like autoantibody-producing B cells, type 1 interferons, and the toll-like receptor 7/9 system, as well as a dysfunctional cell debris clearance and alterations of the FAS system [85]. Many animal models have been developed to study SLE, which more or less resembles human disease [86]. However, due to the great heterogeneity of human disease, it has been proven difficult to translate findings from animal models to humans.

Unfortunately, widely used SLE models, like MLR/lpr or BW mice have not been studied in a functional neuroimmune context to our knowledge. One study merely describes a stable decrease in catecholamine content and sympathetic nerve fibers in the spleen of MLR/lpr mice as compared to control mice [87]. However, there have been 2 studies using lpr/lpr mice also investigating functional consequences of catecholamine alterations. Lpr/lpr mice have a defect in the FAS system and therefore a disturbed regulation of apoptosis, resulting in lymphoproliferative disease and respective increase in size of lymphoid organs, primarily due to expansion of a certain double negative T-cell (CD3+CD4−CD8−) population. Crossed with MLR mice, the FAS defect of lpr mice contributes to an acceleration and aggravation of lupus-like disease in MLR mice, therefore pointing to an importance of the FAS system for the development of lupus [86]. Therefore, neuroimmune results in lpr/lpr mice are somehow related to SLE, however, a direct association is difficult.

On the other hand, lpr/lpr mice are a general model of lymphoproliferation and can be used to study neuroimmune influences on this part of immune function. The clinical effect of peripheral catecholamine depletion in lpr/lpr mice is time dependent, with an increase in mortality and therefore increased lymphoproliferation when peripheral catecholamines were depleted early [39]. Depleting young lpr/lpr mice of sympathetic neurotransmitters in the periphery results in increased immunoglobulin IgM and IgG2a production, earlier onset of lymphoproliferation, and also increased Treg numbers. These results can be explained by increased apoptosis of FAS-deficient lpr/lpr immune cells induced by catecholamines at high concentrations, an effect that will no longer decelerate disease progression when catecholamines are depleted early.

The results of increased immunoglobulins following catecholamine depletion are somewhat in contrast to studies showing that T-dependent activation of naïve, splenic BALB/c B cells in the presence of catecholamines results in B cells producing more Th2-dependent antibodies [21, 88, 89]. However, in the lpr/lpr studies, the authors did not specifically investigate Th2-dependent antibody responses, which hinders direct comparison. In addition, lymphoproliferative disease might alter physiologic response of B cells to neurotransmitters in general, therefore leading to different results. Overall, it seems that FAS-deficient mice, and maybe freshly activated cells in particular, are especially susceptible for catecholamine-induced apoptosis, therefore leading to a decrease in Treg and also in reduced antibody-producing cells. This mechanism might also be part of the anti-inflammatory effect of the SNS during inflammation, as observed in many models (see Tables 1-4). Whether peripheral catecholamines would also be beneficial for SLE remains an open question and needs to be addressed at least in specific mouse models of SLE.

However, there are some hints pointing to an involvement of catecholamines in SLE since chromogranin A and MHPG, both sympathetic activation markers, are increased in the serum of SLE patients [90, 91]. In addition, an increased sympathetic tone to the heart is documented by decreased heart rate variability (HRV) in SLE patients [92‒96]. Furthermore, one recent study clearly showed positive associations of sympathetic HRV parameters with inflammatory markers and lupus disease activity [97].

Rheumatoid Arthritis

Animal models of rheumatoid arthritis (RA) were intensively investigated by several groups in the neuroimmune context. Most RA models are performed in rodents, although there are also valid models in nonhuman primates [98]. There are several spontaneous (mice with susceptible genetic backgrounds: K/BxN, SKG, IL1ra deficient, TNF transgenic) and induced (collagen-induced arthritis [CIA], adjuvant-induced arthritis [AA], DTHA, pristane-induced arthritis, ACPA-induced arthritis, CAIA) animal models for RA; however, the most widely used and studied in the neuroimmune context are CIA and AA (Table 4). CIA is induced by immunizing susceptible mice (mostly DBA1/J) at the base of their tails with bovine type 2 collagen mixed with complete Freund´s adjuvant. CIA is regarded to closely resemble human disease due to chronicity, antibody dependence and arthritis morphology as opposed to AA [98].

As already mentioned above, SNS effects in CIA show a biphasic character with proinflammatory effects in the peri-induction phase and anti-inflammatory effects in the later phases (Table 4) with a transition of the effect during the early phase starting with immunization [51]. Interestingly, central depletion of sympathetic neurons does not have an effect on late CIA, at least in rats [52]; however, central depletion before disease induction has not been investigated so far.

In general, effects of CIA as compared to AA are similar. Both models show a biphasic effect separated by the time point of induction. Since both models depend on innate immunity in this phase, this points to an SNS effect during peri-induction and early phase mediated mainly via an influence on innate immunity. There is also a clear difference in effects of the SNS when regarding local versus systemic effects, with local effects in draining lymph nodes being anti-inflammatory when intervention takes place in the peri-induction phase as opposed to expected proinflammatory effects of the SNS on a systemic level in this phase [56, 57].

Local effects of sympathetic neurotransmitters have also been investigated in the spleens of CIA mice using a superfusion technique, where electrical stimulation leads to quasi physiological release of sympathetic neurotransmitters from sympathetic nerve terminals [53]. Results show that local release of sympathetic neurotransmitters overall leads to a decrease in proinflammatory and an increase in anti-inflammatory cytokines also after the time point of disease induction [41, 47, 50, 53]. At the molecular level, it has also been shown in these superfusion studies that after disease induction βAR-mediated effects become less dominant, whereas αAR-dependent mechanisms are strengthened, which, however, increase proinflammatory mediators locally in the spleen.

A shift in effects on the molecular level is also observed in vivo using the AA rat model, since in this model system, proinflammatory support at the time point of induction is mediated via β2AR, whereas α1AR seems to be anti-inflammatory in this phase, but vice versa in later phases of the disease after the induction time point [40, 55]. Carvedilol blocks sympathetic activity broadly by suppressing signals via βARs and α1AR. In the AA model p.o., treatment with carvedilol starting at disease onset, but not before adjuvant treatment, leads to an amelioration of disease comparable to or even better than achieved with standard treatments like dexamethasone or methotrexate in a dose several times higher than would be used in human RA [42]. However, the AA rat model using a different strain of rats and i.p. instead of oral administration of a more or less specific β2AR agonist, terbutaline leads to a decrease in disease activity. The same is achieved by using an α1AR-antagonist, phentolamine [45]. These on the first glance contradictory results can be conclusively interpreted by a dominance of α1AR proinflammatory mechanisms over anti-inflammatory β2AR-driven mechanisms at least at disease onset and on a systemic level.

Taken together, these results show several important aspects:

Biphasic Effect of the SNS in Relation to Time Point of Inflammation

There is a biphasic effect of the SNS with an overall proinflammatory influence at the pivotal time point of disease induction followed by a gradual shift toward anti-inflammatory effects of the SNS at later time points.

Switch of Adrenergic Receptor Downstream Signaling in Relation to Time Point Inflammation

On a molecular level, this switch from pro- to anti-inflammatory action at the time point of induction of inflammation is reflected by a switch in the downstream effect of adrenoceptor stimulation. In this context, evidence points to a proinflammatory action of βAR and anti-inflammatory action of αAR at the time point of induction and vice versa after that time point (Fig. 1b). The molecular reason for this effect switch is most probably a change in downstream signaling of adrenoceptors as demonstrated under inflammatory conditions in several studies [22, 23].

In AA in rats, β2AR signaling shifts toward MAPK (ERK) signaling during chronic disease because phosphorylation of the β2AR by PKA is reduced and GRK-mediated phosphorylation is increased leading to binding of β-arrestin resulting in β-arrestin-mediated ERK signaling in chronic stage splenocytes [99]. Therefore, overall cAMP increase following β2AR stimulation is impaired depending on disease severity [99]. In CIA, there is also a clear dependence on disease stage, which determines the effect of β2AR stimulation on subsequent signaling pathways, with a predominant p38 MAPK signaling in splenic B cells from arthritic mice starting in early arthritis [23].

Changes in downstream signaling are also observed in human RA synovial cells, where data suggest that under inflammatory conditions, especially hypoxia, Gαs signaling is switched to dominant Gαi signaling in a PDE4/arrestin manner, leading to a nonresponsiveness or even proinflammatory effect of agonists that stimulate these typically Gαs-coupled receptors, like the β2AR [22]. Overall, these changes are all in line with the hypothesis that β2AR signals seem to become less anti-inflammatory and αAR signals become more dominant for immunomodulation of arthritis [40, 41].

Local Role Differs from Systemic Role of the SNS during Inflammation

In this context, it is important to notice that the hard-wired connection of the centrally controlled SNS to cells of the immune system drastically changes when inflammation occurs. In general, sympathetic nerve fibers get repelled from sites of inflammation, which has been shown in several disease models and also in humans [4, 41, 53, 100]. In arthritis, sympathetic nerve fibers are repelled from the synovium of arthritic joints but in systemic inflammation, this retraction of SNS fibers from immune cells also takes place in affected SLOs, like the spleen [41, 53]. The fibers seem not to be destroyed but reordered as, for example, demonstrated in the spleen where a redistribution of catecholaminergic fibers from the white pulp to the red pulp in rat AA is observed [101]. Attempts to inhibit this repulsion as a potential treatment for arthritis have not succeeded so far [43]. However, the earliest time point investigated was 4 days post-induction, which might already be too late to inhibit the repulsion, and as soon as SNS fibers have been reorganized it is hard to restore the situation to before induction. One further consequence of this reordering of sympathetic fibers is that brain controlled effective neurotransmitter concentration at immune cells decreases, which also favors αAR mechanisms over βAR-dependent effects, due to higher affinity for NA to αAR as compared to βAR [9]. However, the consequence of this stop in communication is an uncoupling of centrally controlled SNS activity from local inflammatory processes.

On a systemic level, however, sympathetic relative to parasympathetic activity is increased as indicated, e.g., by increased chromogranin A or neuropeptide Y levels in patients with RA [90, 102] and also by respective data from measurements of HRV or altered cardiac parameters [103, 104]. In addition, a decrease in β2AR expression levels has been observed for CD8+ but not CD4+ T cells in peripheral blood [105], possibly due to an increase in catecholamine exposure during arthritis. In CIA in rats, catecholamines measured in peripheral blood show increased levels starting from the time point of immunization and a normalization of catecholamine levels around day 40 p.i. [52]. On the other hand, intracerebral level of NA in the hypothalamus behave exactly the other way around, with normal levels at the beginning and a sustained increase from day 30 onwards [52], reflecting a reorganization of the whole SNS in the course of arthritis. However, depleting hypothalamic NA in late arthritis has no impact on disease course anymore, probably because at these later stages of arthritis the uncoupling of local regulation of inflammation from centrally coordinated regulation by the brain is already established.

Adrenaline produced in the context of HPA axis activation during acute inflammation has much higher affinity for βARs than NA, which might be an important anti-inflammatory mechanism in the chronic stage of inflammation. However, despite the initial activation of the HPA axis there is no clear increase in adrenal gland activity at later stages of inflammation. On the contrary, there are several mechanisms leading to an inadequate function of the adrenal gland in relation to inflammation, as discussed in detail elsewhere (e.g., see [106]). As opposed to the demonstrated dysbalance between SNS and PNS with a dominance of the SNS during chronic inflammation, there are only a few studies showing differences in the level of hormonal adrenaline in the context of chronic inflammation. In RA, the levels are either unchanged or even decreased [107, 108], which speaks against an important physiological part of adrenaline in modulating chronic inflammation. Nevertheless, adrenaline, due to its very high affinity for βAR as compared to NA, has a role in controlling inflammation [109], and a further decrease might be detrimental.

Local Cells Take Over Sympathetic Control at Sites of Inflammation

Instead of relying on central control for the provision of neurotransmitters at sites of inflammation, and also in SLOs, neurotransmitters are increasingly produced by local ECP capable cells during inflammatory processes [5, 110]. These cells do not necessarily have to be immune cells, and also, e.g., synovial fibroblasts have ECP capabilities (G.P., unpublished work). ECP capable cells have been demonstrated in the inflamed joint and in SLOs by an increase in tyrosine hydroxylase positivity (TH+) [5, 110]. Further studies also proved the dominant anti-inflammatory character of these cells, since artificially generated TH+ cells ameliorate arthritis when used in a treatment approach for CIA mice [44].

In addition, B cells that are capable of ECP act anti-inflammatory by inhibiting T-cell responses and producing the anti-inflammatory cytokine IL-10, which is directly modulated by sympathetic neurotransmitters [6, 49]. Using β2AR-stimulated B cells as treatment in the CIA model also leads to amelioration of disease [46, 49]. It is also important to notice that these TH+ cells are also depleted in the course of chemical sympathectomy with 6-OHDA [44], which is most widely used in neuroimmune research. The anti-inflammatory action of the SNS in later arthritis can therefore also be explained by a depletion of local anti-inflammatory TH+ cells due to artificial sympathectomy, because the SNS on a systemic level still provides at least indirect proinflammatory support also in this phase by, e.g., increasing heart rate, blood flow, extravasation, mobilization and differentiation of leukocytes, liberation of energy-rich fuels, and more [8, 9]. It is also noteworthy, that SNS fibers do not retract completely from sites of inflammation, but only into fatty tissue surrounding the site of inflammation, most probably to provide locally active immune cells with energy-rich fuels [111], which further aids the indirect support of local inflammation by the SNS.

In conclusion and consistent over all model systems and human data, a global model of sympathetic effects in chronic inflammation includes the following considerations (Fig. 2). The SNS together with many other systems like the endocrine system and the immune system is part of a network of body systems that guarantee adaptation and homeostasis. When this network is challenged by a stressor, e.g., by an antigen, it readjusts with the goal of restoring original homeostasis. This is achieved by a standardized stress response, which temporarily leads to a change in network configuration (stress configuration) that prepares the body with the goal of most effectively clearing the stressor, e.g., an antigen during an inflammatory response. To reach this goal, danger has to be sensed in the periphery, e.g., cytokines generate a signal via vagal or sensory afferents which leads among others to activation of the SNS and HPA axes, respectively, with the result of the classical fight and flight reaction.

Fig. 2.

Overall model of sympathetic effects in inflammation. This graphic depicts a general hypothetical model of the effects of the SNS in the context of inflammation. In the acute phase of inflammation (peri-induction), the SNS is activated by signals to the hypothalamus in the brain initiated by inflammatory mediators via vagal or sensory afferents. The increased SNS activity mainly supports inflammation through unspecific systemic contributions, like increase in blood pressure, lymph flow, liberation of energy for immune cells, and recruitment of leukocytes (includes support of immune cell creation in the bone marrow). On a local level, effects are rather immunosuppressive via β-adrenergic mechanisms directly at immune cells. If the inflammation is contained immediately, nothing more needs to be adjusted and the system can fall back into “normal” homeostasis. However, in case the inflammation persists, e.g., because the antigen cannot be effectively cleared, the body network needs to adjust further to optimize the immune response. Therefore, local β-adrenergic inhibition at involved lymphoid organs and at sites of inflammation is decreased by repulsion of sympathetic nerve fibers and a switch of adrenoceptor signals (see also Fig. 1b). In the end, this favors α-adrenergic proinflammatory mechanisms over anti-inflammatory β-adrenergic mechanisms in the post-induction phase. On the systemic level, the increased activity of the SNS as compared to parasympathetic activity is kept upright for continued inflammation support. With a “usual” inflammation, the immune system will be able to clear the antigen after a certain time. However, in the special case of autoimmunity this will not be possible, and the adaptational processes that have been evolutionary selected for short- and medium-term immune interventions continue. This supports the development of known disease sequelae, like increased cardiovascular (CV) risk, prediabetic (increased insulin-resistance due to sympathetic activity) and general catabolic state with, e.g., loss of muscle mass (more information [8]). However, the role of sympathetic pathways for inflammation control is underscored by the additional appearance of endogenously catecholamine producing (ECP) tyrosine hydroxylase (TH+) cells, which are probably not able to control inflammation locally because they may not provide enough catecholamines. They not will be able to stimulate anti-inflammatory β-adrenergic over α-adrenergic mechanisms in the presence of an adrenergic receptor switch from Gαs to Gαi signaling. AR, adrenergic receptor; SLO, secondary lymphoid organ.

Fig. 2.

Overall model of sympathetic effects in inflammation. This graphic depicts a general hypothetical model of the effects of the SNS in the context of inflammation. In the acute phase of inflammation (peri-induction), the SNS is activated by signals to the hypothalamus in the brain initiated by inflammatory mediators via vagal or sensory afferents. The increased SNS activity mainly supports inflammation through unspecific systemic contributions, like increase in blood pressure, lymph flow, liberation of energy for immune cells, and recruitment of leukocytes (includes support of immune cell creation in the bone marrow). On a local level, effects are rather immunosuppressive via β-adrenergic mechanisms directly at immune cells. If the inflammation is contained immediately, nothing more needs to be adjusted and the system can fall back into “normal” homeostasis. However, in case the inflammation persists, e.g., because the antigen cannot be effectively cleared, the body network needs to adjust further to optimize the immune response. Therefore, local β-adrenergic inhibition at involved lymphoid organs and at sites of inflammation is decreased by repulsion of sympathetic nerve fibers and a switch of adrenoceptor signals (see also Fig. 1b). In the end, this favors α-adrenergic proinflammatory mechanisms over anti-inflammatory β-adrenergic mechanisms in the post-induction phase. On the systemic level, the increased activity of the SNS as compared to parasympathetic activity is kept upright for continued inflammation support. With a “usual” inflammation, the immune system will be able to clear the antigen after a certain time. However, in the special case of autoimmunity this will not be possible, and the adaptational processes that have been evolutionary selected for short- and medium-term immune interventions continue. This supports the development of known disease sequelae, like increased cardiovascular (CV) risk, prediabetic (increased insulin-resistance due to sympathetic activity) and general catabolic state with, e.g., loss of muscle mass (more information [8]). However, the role of sympathetic pathways for inflammation control is underscored by the additional appearance of endogenously catecholamine producing (ECP) tyrosine hydroxylase (TH+) cells, which are probably not able to control inflammation locally because they may not provide enough catecholamines. They not will be able to stimulate anti-inflammatory β-adrenergic over α-adrenergic mechanisms in the presence of an adrenergic receptor switch from Gαs to Gαi signaling. AR, adrenergic receptor; SLO, secondary lymphoid organ.

Close modal

In this phase, the SNS provides proinflammatory support on a systemic level, e.g., by increasing blood flow and pressure, increasing lymph flow, liberating leukocytes from vessel walls, liberating energy-rich fuels (catabolism), and more (Fig. 2, peri-induction). However, on a local level, e.g., in SLOs, high sympathetic activity leads to immunosuppression due to high catecholamine concentrations, which favor β2AR cAMP increasing signals to immune cells (Fig. 2, peri-induction). If the stressor, e.g., the antigen is eliminated fast enough, no further adaptations need to be conducted and SNS as well as HPA axis reduce their activity to normal and the network falls back into the original “healthy” homeostasis.

However, if the stressor cannot be removed immediately, further adaptational processes need to occur to secure elimination of the antigen. Since the high systemic sympathetic activity is kept upright, sympathetic nerve fibers need to be retracted to reduce anti-inflammatory local effects to assure optimal immune efficacy (think of an infectious intruder). This configuration now provides maximum support for fast elimination of the antigen (Fig. 2, post-induction). However, if the stressor is still not eliminated, the network falls into a new “diseaseostasis,” or as it was called by others “cacostasis” [13] (from Greek: kakos = bad), where the high sympathetic activity is kept upright on a systemic level, but locally sympathetic neurotransmitter concentrations are now regulated by local ECP capable cells, e.g., immune cells (Fig. 2, post-induction). In addition, adrenoceptor downstream signals are altered and shifted away from classical cAMP signals toward MAPK signaling pathways (p38, ERK). This pathologic cacostasis is the situation found in the context of autoimmune diseases, since these conditions show chronic inflammation, e.g., due to an autoantigen that cannot be completely eliminated. Which receptor subtypes can be targeted in this context to support amelioration of inflammation is not finally clear; however, it seems that antagonism at α1AR as well as agonism at β2AR might be a good choice [40].

However, there are already therapeutic approaches based on these NEI concepts, e.g., apremilast, a drug that blocks the degradation of cAMP by inhibiting phosphodiesterases in immune cells, leading to immunosuppression and is currently successfully used in the clinical context of psoriatic arthritis (e.g., [112]). Also, the effect of methotrexate is partly based on an increase in cAMP by blocking an adenosine degrading enzyme and leading to increased activation of adenosine receptors, like A2A/B, which subsequently increase cAMP in receptor bearing immune cells [113, 114]. Adenosine is also a sympathetic co-transmitter and therefore released during activation by sympathetic nerve terminals to modulate inflammation by adenosine receptors [115]. The importance of the adenosine system is evident by recent findings of a specific defect in CD73, an adenosine generating enzyme on SLE B cells, possibly contributing to increased pathologic B-cell activation [116]. In addition, inhibitors of catecholamine-degrading monoamino-oxidases types A and B could act anti-inflammatory with first positive results in RA [117].

Besides directly acting on neurotransmitters, their receptors or second messengers, another possibility is to rebalance the ANS. The most straight forward way to equalize the relative increase in sympathetic activity is to increase parasympathetic activity. This can be done indirectly by using relaxing techniques, like meditation, yoga, Thai Chi, or similar, which support regaining autonomic balance and suppression of inflammation, e.g., in autoimmune diseases (reviewed in [118]). The other way is, to directly stimulate the vagal nerve, which is an already established technique for other disease entities like adjunctive therapy for refractory epilepsy or depression, respectively. There are also several pieces of evidence that show promising results across autoimmune diseases (reviewed in [119, 120]). Overall, these are promising results meriting further study.

The authors state that they have no conflict of interest regarding the content of this manuscript.

This review article was not funded by any third party.

Georg Pongratz drafted and conceptualized the manuscript. Rainer H. Straub critically revised the manuscript for important intellectual content. All authors finally approved the published version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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