Neural control of the spleen as an effector of immune responses to inflammation: mechanisms and treatments

Abstract

Immune system responses are a vital defense mechanism against pathogens. Inflammatory mediators finely regulate complex inflammatory responses from initiation to resolution. However, in certain conditions, the inflammation is initiated and amplified, but not resolved. Understanding the biological mechanisms underlying the regulation of the immune response is critical for developing therapeutic alternatives, including pharmaceuticals and bioelectronic tools. The spleen is an important immune effector organ since it orchestrates innate and adaptive immune responses such as pathogen clearance, cytokine production, and differentiation of cells, therefore playing a modulatory role that balances pro- and anti-inflammatory responses. However, modulation of splenic immune activity is a largely unexplored potential therapeutic tool that could be used for the treatment of inflammatory and life-threatening conditions. This review discusses some of the mechanisms controlling neuroimmune communication and the brain-spleen axis.

INTRODUCTION

The spleen is a sentinel organ that continuously monitors the blood for pathogens, clears the blood of defective cells and microorganisms, stores platelets and immune cells, and initiates immune responses to antigens (1–3). Immune cells residing in the spleen are recruited to fight diseases and infections and a balance between proinflammatory and anti-inflammatory status in the spleen is crucial for the elimination of pathogens without harming the host. In this review, we highlight the neural mechanisms controlling the immunological function of the spleen and their clinical implications with a focus on autonomic regulation.

INNERVATION OF THE SPLEEN

The spleen is virtually devoid of sensory innervation, with the exception of rare afferent fibers from dorsal root ganglia (DRG) neurons that putatively innervate the splenic vasculature near the hilar region (4). The specific sensory stimuli detected by these rare afferent fibers and the functional role of this input are unknown. An alternative mechanism by which the spleen conveys signals to other organs is via a humoral route, i.e., by cell emigration, cytokines, and chemokines exiting the spleen through the venous and lymphatic circulation (1).

The spleen is innervated by the splenic nerve, which is composed of sympathetic noradrenergic fibers (5, 6) originating from the celiac ganglion (CG), suprarenal ganglia (SRG), and the thoracic sympathetic chain (4, 7, 8). Only sparse parasympathetic fibers are found in the spleen (9–12). Because there are technical experimental difficulties in specifically targeting vagal nerve pathways to the spleen, the functional implications of a direct parasympathetic innervation of the spleen are still debated (13, 14). Although it is generally accepted that the CG and SRG are innervated by sympathetic and parasympathetic fibers (8, 15–18), it is controversial whether splenic ganglion cells in the CG and SRG receive vagal inputs (8, 19) (Fig. 1). More studies are necessary to clarify whether there is a functional neural connection between parasympathetic nerve fibers and splenic sympathetic ganglion cells.

Figure 1.

Neural control of the spleen during endotoxemia. Bacterial antigens elicit a systemic inflammatory response. Cells and humoral factors emigrate from the spleen to the circulation and other organs. Inflammatory factors activate brain-mediated responses potentially via humoral (blood-brain-barrier, BBB, and circumventricular organs, CVOs) and neural routes (vagal and carotid sinus nerve afferents). Corticotropin-releasing hormone (CRH) neurons in central amygdala (CeA) and paraventricular nucleus (PVN) modulate adaptive immune responses to stress while ventral tegmental area (VTA) neurons modulate innate immune responses to bacteria. Peripheral afferents from the IX and X cranial nerves synapse with second-order neurons in the nucleus tractus solitarius (NTS), which can activate C1 neurons in the rostral ventrolateral medulla (RVLM) and neurons in the dorsal motor nucleus of the vagus (DMV). RVLM neurons synapse with preganglionic neurons in the intermediolateral column of the spinal cord (IML), including those giving rise to axons that form the splanchnic nerves. Axons from sympathetic ganglion cells in the celiac and suprarenal ganglia form the sympathetic splenic nerve, which nerve terminals release norepinephrine (NE) and neuropeptide Y (NPY). Choline acetyltransferase (ChAT)-expressing T-cells release acetylcholine (ACh) in response to β2-adrenergic receptor (AR) activation, leading to activation of α7 nicotinic receptor (α7nAChR) in macrophages. α7nAChR signaling blocks TNF-α release, thus reducing inflammation. β2-AR and NPY receptors (NPY-R) activation in immune cells reduces TNF-α production and β2-AR activation increases IL-10 release during inflammation. Afferent vagus nerve stimulation induces anti-inflammatory effects via increasing splenic nerve activity. Vagal efferent fibers send projections to sympathetic ganglia and viscera that, when stimulated, reduce inflammatory responses via β2-AR and α7nAChR. Dashed lines represent controversial or yet to be clarified pathways.

ROLES FOR NOREPINEPHRINE AND NEUROPEPTIDE Y IN SPLENIC FUNCTION

Catecholaminergic fibers innervate both the parenchymal cells and the blood vessels of the spleen, thereby contributing to the splenic influence on immune functions. Approximately 80% of catecholaminergic CG neurons coexpress neuropeptide Y (NPY) (17). Within the spleen, tyrosine hydroxylase (TH)⁺ nerve fibers that colocalize with NPY densely innervate the splenic vasculature and provide a minor innervation of the splenic parenchyma (17). Splenic nerve terminals can release norepinephrine (NE), NPY, and other neurotransmitters (20–23). Studies using rodents show that a reduction in blood flow initiated by the release of NE from nerve terminals surrounding splenic blood vessels contributes to local hypoxia in immune cells and blocks leukocyte interstitial migration, which suppresses immune responses to tumors and to viral and parasitic infections in an α1-adrenoreceptor (AR) and β2-AR-dependent fashion (21). However, during endotoxemia, endogenous interleukin (IL)-1β acting locally, in the spleen, increases splenic blood flow despite an increased splenic nerve activity (24, 25). The mechanisms by which IL-1β increases splenic blood flow in the presence of elevated splenic nerve activity are unknown.

Studies using confocal analysis and electron microscopy showed that TH nerve terminals within the spleen form synapse-like structures with B and T cells, which could induce and regulate immune responses (26–28), although release of NE from varicose axon terminals that are not in close proximity with immune cells may also play a role in modulating immune cell function in a paracrine fashion (29). In general, B and T cells express the β2-AR and innate immune cells, such as macrophages, express β2-AR, α1-AR, and α2-AR (30, 31). The β2-AR plays a critical role in the suppression of tumor necrosis factor (TNF)-α and increase of IL-10 secretion by immune cells (32–34), possibly via a noncanonical phosphatidylinositol 3-kinase (PI3K) intracellular pathway (35, 36). Many of these events are thought to occur in the spleen (37–40) (Fig. 1). In addition, splenic nerve activity and β2-AR activation protect against endotoxemia-induced hypotension and hypovolemia, improving survival (33, 34, 41). Overall, the sympathetic control of splenic function is important to modulate immune and cardiovascular functions, preventing cardiovascular collapse during endotoxemia.

Activation of ganglionic NPY neurons innervating the spleen attenuates the production of pro-inflammatory cytokines. Yu et al. (22) showed that NPY mRNA is expressed in both the SRG and CG neurons and that spleen-projecting neurons in SRG and CG express the Toll-like receptor (TLR)-4. Lipopolysaccharide (LPS), a surface membrane component of Gram-negative bacteria, is a TLR4 agonist. Direct application of LPS increases calcium influx in SRG-CG and peripheral administration of LPS upregulates NPY mRNA there (22). These data suggest that LPS activates NPY-expressing neurons that send inputs to the spleen. Neuronal NPY attenuates the production of proinflammatory cytokines in the spleen in response to LPS or in arthritis via NPY receptors (NPY-R) in the spleen and improves survival in septic mice (22). These data reveal a therapeutic potential for NPY-R agonists in modulating inflammation by acting on NPY-R on splenic macrophages and T-cells (22) (Fig. 1).

NEURAL REFLEXES MODULATING SPLENIC IMMUNE FUNCTION

The brain can control the production of cytokines in the spleen via the splenic nerves. The spleen is a substantial source of cytokines, such as TNF-α, in the circulation during systemic inflammation, as elucidated by studies in which surgical removal of the spleen largely reduces the initial increases in plasma TNF-α levels in response to systemic inflammation (38, 42, 43). Consequently, a blockade of TNF-α production in the spleen (as occurs with a central nervous system-driven increase in splenic nerve activity) causes a reduction in the release of TNF-α into the circulation.

Systemic inflammation activates a sympathetic neural pathway that reduces the production of inflammatory cytokines, including TNF-α, in the spleen (and other abdominal organs) during endotoxemia via the splanchnic nerves (44). Therefore, interruption of the sympathetic outflow to the spleen potentiates the inflammatory response to bacterial endotoxin (45). In agreement, loss of noradrenergic innervation to the spleen dysregulates splenic function and compartmentalization of immune cells in the spleen (26). Postmortem analyses showing the loss of noradrenergic nerve fibers in the spleen of septic patients are consistent with the interpretation that impaired neuroimmunomodulation of splenic function can predispose such patients to lethal immune responses (46).

In acute responses to endotoxemia, the endogenous pathways that restrain inflammatory responses do not require the parasympathetic nerves (Fig. 1). Cervical vagotomy, unlike transections of the splanchnic nerves, does not potentiate systemic inflammation or block increases in splanchnic or splenic sympathetic nerve activity during endotoxemia (45), which suggests that the vagus nerve is not required for restraining an endogenous immune response to acute systemic inflammation. Interestingly, vagus nerve stimulation has potent anti-inflammatory effects (discussed in therapeutic modulation of the immune function in the spleen below). It remains to be determined if, even in the absence of distal vagal fibers, inflammatory signals from the periphery can reach the cell bodies of vagal sensory neurons and thereby modulate autonomic reflexes regulating splenic function. It is important to point out that different immune challenges may elicit conserved and/or different body responses. Therefore, the findings from a particular animal model may not apply to all inflammatory conditions.

SENSORY PATHWAYS MODULATE INFLAMMATORY CYTOKINES LEVELS IN THE SPLEEN DURING SYSTEMIC INFLAMMATION

Both neural and humoral pathways are thought to convey information about the peripheral inflammatory status to the brain, and thereby modulate splenic immune functions via the splenic nerves. Here, we describe a few of the sensory neuroimmune pathways that may regulate the brain networks controlling immune function in the periphery.

Humoral Pathways

At least three humoral pathways may contribute to modulating the autonomic nervous system during an immune challenge. Circulating cytokines and bacterial endotoxins change blood-brain-barrier (BBB) permeability (47, 48) and can reach the brain parenchyma via the BBB (49–54). Brain areas lacking the BBB, such as the circumventricular organs (CVOs), are a potential target for inflammatory mediators to modulate the activity of neurons (55–59). In the absence of a breach in BBB, brain endothelial cells play a crucial role in the translation of inflammatory signals to neuronal activity, as occurs in bacterial fever (60, 61).

The increases in splenic nerve activity during endotoxemia are at least partially mediated by derivatives of arachidonic acid in the brain. Intracerebroventricular pretreatment with a cyclooxygenase inhibitor, which prevents the enzymatic conversion of arachidonic acid to functional derivatives, such as prostaglandin E₂ (PGE₂), significantly delays or abolishes the onset of LPS-evoked increases in splenic nerve activity (62). PGE₂ also plays a critical role in bacterial fever (63). Pretreatment with an intracerebroventricular injection of PGE₂ increases splenic sympathetic nerve activity and attenuates endotoxemia-induced splenic TNF-α expression (62, 64) (Fig. 1). Thus, PGE₂ acts as a regulatory mediator serving to drive a fever response while also suppressing a splenic immune response. This balancing of the immune responses is important for ensuring the elimination of the invading pathogen while at the same time limiting damage to the host, and further has important implications for the use of pharmacological therapeutic approaches.

Nodose Ganglia Neurons and Vagus Nerve

Vagal sensory neurons located in the nodose ganglia are activated by inflammatory stimuli. Circulating inflammatory cytokines, such as IL-1β and TNF-α, lead to increases in afferent vagus nerve activity in rodent models (65–67). Another index of the vagal afferent nerve activation in response to cytokines is the expression of c-fos mRNA in neurons in the nodose ganglion following intravenous injection of IL-1β (66). However, cervical vagotomy does not prevent inflammation-induced production of c-Fos protein in the nucleus tractus solitarius (NTS) (68), where the primary vagal afferent fibers make synaptic contact with second-order neurons (69). NTS neurons also receive inputs from other sensory fibers, such as spinal afferents and glossopharyngeal afferent axons, which could be contributing to an elevated production of c-Fos independently of an excitatory vagal input. For instance, a putative role for renal afferents in the reflex regulation of immunity has been reviewed elsewhere (70). Considering that TLR4, IL-1 receptor, and PGE₂ receptor (EP3) mRNAs are expressed in the nodose ganglia (66, 71, 72), inflammatory signals from the periphery may directly affect vagal sensory neurons at the level of the soma, independent of vagal afferent fiber activity. Supporting this notion, LPS induces production of calcitonin gene-related peptide (CGRP), a neurotransmitter produced by vagal sensory neurons, in nodose-jugular ganglia culture in a TLR4-dependent fashion, suggesting that vagal sensory neurons are directly responsive to inflammatory antigens (67, 71, 73). The role of vagal afferent fibers and nodose ganglia neurons in mediating an endogenous immune response via autonomic pathways still needs to be determined. In contrast, it has been shown that electrical stimulation of vagal afferents suppresses systemic inflammation likely via reflex activation of the splanchnic nerves (74). Activation of vagal afferents after high-fat enteral nutrition also produces anti-inflammatory effects during endotoxemia and hemorrhagic shock (75, 76).

Carotid Body: Is the Carotid Sinus Nerve an Afferent Pathway Regulating Splenic Immune Function?

The carotid bodies play a role in inflammatory responses. Cells in the carotid body express cytokine receptors, and inflammation increases carotid sinus nerve activity (77–80). In agreement, the chemoreflex response to potassium cyanide is potentiated by LPS, which may indicate that carotid sinus nerve activity is facilitated during systemic inflammation (81). It was shown recently that carotid body denervation increases mortality in septic rats and increases circulating cytokine levels in response to TNF-α (77, 82, 83). Thus, the carotid body is necessary for restraining inflammation induced by TNF-α, likely via a reflex activation of the splanchnic nerves (77) (Fig. 1).

Based on changes in splenic NE content, it was suggested that the spleen is one of the effector organs in the carotid body-splanchnic nerves reflex (77). However, changes in NE levels in the spleen do not only depend on splenic nerve activity but also on the turnover rate and perhaps on blood levels of NE since increased plasma NE levels are detected for at least 2 h after administration of TNF-α in subjects (84). Therefore, more studies are necessary to clarify if the spleen plays a role in the anti-inflammatory effects of the carotid body-splanchnic nerves reflex. Interestingly, electrical stimulation of the carotid sinus nerve reduces systemic inflammation via glucocorticoid receptors in immune cells, and at least part of this effect does not require the spleen (85). The interplay between the carotid sinus nerve and immune function is likely to be complex and requires further research to be more completely understood.

BRAIN AREAS CONTROLLING THE AUTONOMIC OUTFLOW TO THE SPLEEN

Anatomical studies in rodents using neuronal tracing showed several brain areas that are polysynaptically connected to the spleen (18, 86), presumably via the splenic sympathetic nerve. Little is known, however, about the functional aspects of the brain networks that control the immunological function of the spleen. Here, we highlight a few players in the brain-spleen axis (Fig. 1).

Both the NTS and the rostral ventral lateral medulla (RVLM) contain neurons that are polysynaptically connected to the spleen (18). Neurons in the NTS receive and integrate sensory information from peripheral nerves (including vagi and carotid sinus nerve), as well as from other CNS sites, and densely innervate neurons in the RVLM. In turn, RVLM neurons send rostral and caudal projections that both regulate and contribute to the sympathetic premotor input to the spinal cord. Indeed, an NTS-RVLM-splanchnic nerve pathway appears to participate in a sympathetic reflex elicited by the carotid sinus nerves in response to circulating TNF-α (77), but the role of the spleen as an effector in this reflex remains to be elucidated. Optogenetic stimulation of C1 neurons, a population of sympathetic premotor neurons in the RVLM, reduces kidney damage in a renal ischemia-reperfusion model likely via increasing the sympathetic outflow to the spleen (87, 88). A putative NTS-RVLM (C1) pathway does not exclude other brain areas that could modulate splenic immune function during inflammation. In fact, supramedullary inputs provide a significant tonic excitatory input to NTS neurons and contribute to their spontaneous and vagus nerve-driven activity (89).

LPS increases the expression of inflammatory cytokines not only in the NTS but also in other brain areas that contribute to the control of autonomic functions such as the paraventricular nucleus (PVN), central amygdala (CeA), NTS, and dorsal motor nucleus of the vagus (DMV) (90). Stimulation of other brain areas that are polysynaptically connected to the spleen, such as the CeA and the PVN, as well as the ventral tegmental area (VTA), which may not be connected to the spleen (18, 86), leads to increased splenic immune cell activity. Stress modulates splenic adaptive immunological responses via differentially modulating corticotropin-releasing hormone (CRH)-expressing neurons in CeA or PVN. Optogenetic activation of CeA^CRH or PVN^CRH neurons increases splenic sympathetic nerve activity and increases a splenic adaptive immune response, plasma cell formation (91). In addition, an intracerebroventricular injection of CRH increases the content of NE in the spleen and intracerebroventricular injection of a CRH antagonist reduces splenic NE in response to an intravenous injection of IL-1β (92). These findings show that CRH within the CNS contributes to the increase in sympathetic outflow to the spleen during systemic inflammation induced by IL-1β, thus participating in the regulation of splenic function. The precise pathways by which CRH neurons modulate splenic nerve activity remain unknown. The humoral component of the brain-spleen axis via the hypothalamus-pituitary-adrenal axis has been extensively reviewed elsewhere (93, 94). In addition, chemogenetic activation of VTA neurons increases immune cell activation and reduces bacteria survival (95), and these effects were prevented by chemical denervation of catecholaminergic splenic nerve fibers in rats (95). This indicates that a fine regulation between immune cell activation for bacterial clearance and inhibition of immune cell activity for preventing an exaggerated inflammatory response is likely to be mediated by the brain.

Only a few neurons located in the dorsal motor nucleus of the vagus (DMV) of some rats were transsynaptically labeled following pseudorabies virus (a transsynaptic retrograde tracer) injection in the spleen (18). Nonetheless, optogenetic stimulation of cholinergic neurons in the DMV increases splenic nerve activity and reduces circulating TNF-α levels during endotoxemia (19). The pathway comprising the cholinergic DMV neurons (vagal efferent fibers) that act to reduce systemic inflammation has been referred to as the “cholinergic anti-inflammatory pathway” and has been shown to be an efferent arm of a CNS circuit regulating the brain-spleen axis during systemic inflammation (19, 96).

Together, these studies show that activations of specific nuclei in the brain can increase splenic nerve activity and regulate immune function in the spleen. Interestingly, the splenic nerve-mediated effects can either decrease cytokine production by immune cells or recruit immune cells for the initiation of immune responses, suggesting that the brain can differentially regulate the splenic response. The specific conditions under which these diverse effects occur and the mechanisms underlying these effects are important areas for future studies.

A SPLEEN-TO-LIVER HUMORAL PATHWAY MODULATES INFLAMMATION

The splenic venous vasculature collects into the splenic vein that drains into the hepatic portal system (3, 97). This arrangement permits a unique hormonal communication axis between the spleen and liver that is particularly important during endotoxemia in which the number of neutrophils and macrophages in the liver increases (98). These cells are likely supplied by blood myeloid cells from the spleen since splenectomy reduces the number of macrophages in the liver and the levels of TNF-α in the portal vein and vena cava in response to LPS (98–100). These and other data validate the decades-old proposal that “splenic factors” are necessary for increasing Kupffer cell responsivity to endotoxin (101, 102).

Recently, leukotriene B4 from the spleen was demonstrated to sensitize Kupffer cells to secrete TNF-α in response to LPS (100). In addition, splenectomy reduces plasma TNF-α and Tnf gene expression in the liver while partial hepatectomy reduces plasma TNF-α without affecting Tnf gene expression in the spleen (100). These data reveal a unidirectional spleen-to-liver humoral axis influencing hepatic function in systemic inflammation (100) (Fig. 1). Indeed, leukotriene B4 receptor antagonists have emerged as therapeutic targets for the treatment of inflammatory diseases (103), but whether the anti-inflammatory effects of leukotriene B4 receptor are mediated by the spleen-liver axis is not known. Interactions of the spleen with other players such as the gut, gut microbiota, and higher cerebral functions have been reviewed recently elsewhere (104, 105).

THERAPEUTIC MODULATION OF THE IMMUNE FUNCTION IN THE SPLEEN

The noteworthy effects of the sympathetic (44) and parasympathetic (106) nervous systems in controlling immunological function and recent advances concerning the mechanisms regulating lethal inflammatory responses have opened new avenues for preclinical and clinical research focused on therapeutic approaches to inflammatory diseases, such as endotoxemia, sepsis, hemorrhagic shock, respiratory conditions, rheumatoid arthritis, obesity, and type 2 diabetes (106–109). Many of these inflammatory conditions can be ameliorated by using noninvasive techniques, such as ultrasound (110), acupuncture (111), laser acupuncture (112), electroacupuncture (113, 114), and pharmacotherapy, as well as by using invasive techniques, such as implantable stimulating electrodes surrounding nerves (115, 116). Here, we will discuss a few of these therapies and their mechanisms of action.

Anti-Inflammatory Effects of Vagus Nerve Stimulation

VNS ameliorates inflammatory diseases such as endotoxemia, sepsis, hemorrhagic shock, respiratory or intestinal inflammatory conditions, and, potentially, rheumatoid arthritis (109, 117–120). Selective stimulation of vagal afferent or efferent fibers induces anti-inflammatory effects by distinct neural pathways (40, 87). Interestingly, the anti-inflammatory effects of both afferent and efferent vagus nerve stimulation (VNS) require β2-AR activation (40). In contrast, only efferent VNS requires choline acetyltransferase (ChAT)-expressing T-cells (40). In this scenario, efferent, but not afferent, VNS activates acetylcholine (ACh) release from ChAT T-cells upon reflex adrenergic stimulation, then binding of ACh to α7 nicotinic receptors (α7nAChR) in splenic macrophages inhibits NF-κB phosphorylation, thus reducing TNF-α production (121–124). In addition, efferent VNS reduces intestinal inflammation via the enteric nervous system and resident macrophage α7nAChR in the gut independently of the spleen and T-cells (125, 126).

The anti-inflammatory effects of cervical afferent VNS are not prevented by subdiaphragmatic vagotomy or by blockade of muscarinic acetylcholine receptors (mAChRs) (87). Thus, afferent VNS does not require efferent vagus nerve fibers. Vagal afferent fibers can modulate immune function via the sympathetic nervous system, by reflexively activating the splanchnic and splenic nerves (8, 74, 87). The protective and anti-inflammatory effects of afferent VNS require C1 catecholaminergic neurons, located in the RVLM, whereas efferent VNS does not (87). A hypothesis for a neural circuit mediating the effects of afferent VNS on splenic sympathetic outflow is that vagal afferents activate NTS neurons, which project to C1 sympathetic premotor neurons to increase the sympathetic outflow to the spleen and other organs to induce anti-inflammatory effects. This hypothetical circuit does not exclude other brain areas that could modulate the immune function of the spleen.

Anti-Inflammatory Effects of Pharmaceuticals

Peripherally acting drugs can be beneficial for reducing splenic inflammatory responses. Based on the anti-inflammatory effects of NPY overexpression in SRG and CG neurons and the proinflammatory effects of NPY knockdown (22), activation of splenic NPY-R by administration of an NPY-R agonist is a potential therapeutical tool to reduce inflammation and sepsis mortality (22).

Altering the relevant brain circuits could also modulate splenic function. Centrally acting mAChR agonists and an acetylcholinesterase inhibitor, galantamine, reduce mortality and systemic inflammation in septic mice. The anti-inflammatory effect was absent in mice that were subjected to splenic neurectomy (127, 128), splenectomy (128, 129), or in α7nAChR knockout mice (128). Interestingly, galantamine reduced body weight in addition to reducing inflammatory cytokines in high-fat diet-fed mice (130). The brain networks underpinning the effects of centrally acting cholinergic drugs in inflammation and metabolism are not known.

Modulation of the neurotransmitter and hormone serotonin is also a promising treatment for neural and peripheral inflammation. In the LPS model of bacterial infection, administration of an antidepressant drug (fluoxetine, a selective serotonin reuptake inhibitor), reduces plasma and splenic cytokine (TNF-α, IL-1β, and IL-6) levels and the expression of c-Fos and TNF-α mRNA in the PVN and the NTS (90). Chronic subdiaphragmatic vagotomy partially reverses the anti-inflammatory effects of fluoxetine in the periphery, but not in the brain (90). Our previous studies show that intracerebroventricular administration of serotonin reduces plasma TNF-α, IL-1β, and IL-6 and splenic TNF-α and IL-10 levels, prevents hypotension, and reduces corticosterone levels in endotoxemia (131, 132). These effects may be mediated by the splanchnic nerves since serotonin receptor agonists increase splanchnic nerve activity (133). As pointed out earlier, the splanchnic nerves control a sympathetic reflex with anti-inflammatory properties (134). Whether the anti-inflammatory effects of serotonin are mediated specifically by the splanchnic and/or splenic nerves and the neural circuits mediating these effects remain to be determined.

CONCLUSION

Elucidating the CNS neuroimmune pathways controlling splenic function is important for the development of anti-inflammatory therapies that act to modulate a splenic immune response or mimic sympathetic neural activity to the spleen. Neurochemical modulation of these central autonomic nervous system circuits could be of potential benefit to patients with inflammatory conditions such as arthritis, kidney injuries, sepsis, and endotoxemic shock.

GRANTS

This study was supported by the National Institutes of Health Grant DK112198 (to C.J.M.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

C.M.D.M. and C.J.M. conceived and designed research; C.M.D.M. prepared figure; C.M.D.M. drafted manuscript; C.M.D.M. and C.J.M. edited and revised manuscript; C.M.D.M. and C.J.M. approved final version of manuscript.