Autonomic Neuroscience: Basic and Clinical 182 (2014) 83–88

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Neural regulation of gastrointestinal inflammation: Role of the sympathetic nervous system Andrea L. Cervi a, Mark K. Lukewich a, Alan E. Lomax a,b,⁎ a b

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada Department of Medicine, Gastrointestinal Diseases Research Unit and Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada

a r t i c l e

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Article history: Received 14 November 2013 Accepted 11 December 2013 Keywords: Neuroimmunology Sympathetic nervous system Gastrointestinal tract

a b s t r a c t The sympathetic innervation of the gastrointestinal (GI) tract regulates motility, secretion and blood flow by inhibiting the activity of the enteric nervous system (ENS) and direct vasoconstrictor innervation of the gut microvasculature. In addition to these well-established roles, there is evidence that the sympathetic nervous system (SNS) can modulate GI inflammation. Postganglionic sympathetic neurons innervate lymphoid tissues and immune cells within the GI tract. Furthermore, innate and adaptive immune cells express receptors for sympathetic neurotransmitters. Activation of these receptors can affect a variety of important immune cell functions, including cytokine release and differentiation of helper T lymphocyte subsets. This review will consider the neuroanatomical evidence of GI immune cell innervation by sympathetic axons, the effects of blocking or enhancing SNS activity on GI inflammation, and the converse modulation of sympathetic neuroanatomy and function by GI inflammation. © 2013 Elsevier B.V. All rights reserved.

1. Introduction The cell bodies of sympathetic preganglionic neurons are located in the intermediolateral cell column of the thoracolumbar spinal cord. The axons of these cholinergic neurons synapse on postganglionic neurons located in paravertebral and prevertebral ganglia, as well as adrenal chromaffin cells (Janig and McLachlan, 1987; Szurszewski and Miller, 1994). The majority of postganglionic sympathetic neurons that innervate the gastrointestinal (GI) tract have cell bodies in the large prevertebral ganglia of the abdomen, which include the celiac, superior mesenteric and inferior mesenteric ganglia (Szurszewski and Miller, 1994; Miolan and Niel, 1996; Lomax et al., 2010). These ganglia are centres of convergence for a number of central and peripheral inputs, including preganglionic axons, neighbouring postganglionic sympathetic neurons, axon collaterals from spinal afferent neurons, and a special subset of enteric neurons called intestinofugal neurons (Szurszewski and Miller, 1994; Miolan and Niel, 1996; Lomax et al., 2000). The major neurotransmitter released from sympathetic postganglionic nerve terminals in the gut is noradrenaline (NA), though ATP and neuropeptide Y (NPY) can also participate in sympathetic neurotransmission within the GI tract (Lundberg et al., 1989; Evans and Surprenant, 1992). The axons of postganglionic sympathetic neurons ramify within the serosal surface of the intestine and innervate several GI tissues, including vascular beds and the enteric nervous system (ENS). There is also ⁎ Corresponding author at: GIDRU wing, Kingston General Hospital, 76 Stuart Street, Kingston, ON K7L 2V7, Canada. E-mail address: [email protected] (A.E. Lomax). 1566-0702/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autneu.2013.12.003

some evidence of sympathetic nerve terminals within the mucosa and the gut associated lymphoid tissues (GALT), although other investigators did not detect sympathetic axons in mucosal tissues other than the vasculature and muscularis mucosae (Furness, 1970; Felten et al., 1992; Kulkarni-Narla et al., 1999; Elenkov et al., 2000; Straub et al., 2006). Activation of α2-adrenergic receptors (ARs) on neurons within the myenteric plexus inhibits intestinal motility via pre- and postsynaptic signalling mechanisms (Hirst and McKirdy, 1974; North and Surprenant, 1985). Furthermore, signalling to α2-ARs on submucosal neurons reduces mucosal electrolyte secretion (Sjovall et al., 1983a,b). ATP and NA released from perivascular sympathetic varicosities stimulate vasoconstriction of GI arterioles (Evans and Surprenant, 1992; Lomax et al., 2007), which is important in regulating blood flow to the mucosa (Lundgren, 1984; Vanner and Surprenant, 1996). 2. Distribution of sympathetic axons in immune tissues Postganglionic sympathetic axons project to every primary and secondary lymphoid organ in the body, where they are found in close proximity to parenchymal immune cells (Williams and Felten, 1981; Bulloch and Pomerantz, 1984; Felten et al., 1987; Nance and Burns, 1989; Romeo et al., 1994). For example, histofluorescence studies conducted on the spleen revealed the presence of noradrenergic fibres, mainly originating from the superior mesenteric ganglion (SMG), in vascular and trabecular plexuses (Williams and Felten, 1981; Felten et al., 1985, 1987). Sympathetic axons radiate from these plexuses into areas of T lymphocyte accumulation termed the lymphatic sheath. Macrophages and B lymphocytes closely appose these T lymphocyte-rich regions and thus also receive noradrenergic innervation (Felten et al.,

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1987). Within the gut, sparse noradrenergic fibres terminate in the lamina propria among fields of lymphoid cells that are not associated with blood vessels. The greatest innervation density is found in areas of T lymphocyte aggregation (Felten et al., 1985; Kulkarni-Narla et al., 1999). This same innervation pattern has also been observed in Peyer's patches, which are small intestinal aggregates of lymphoid follicles (see Bellinger and Lorton, this issue of Autonomic Neuroscience). Ultrastructural studies of sympathetic varicosities in lymphoid tissues revealed that sympathetic terminals do not make traditional synaptic contacts with immune cells (Williams and Felten, 1981; Felten et al., 1987; Felten and Felten, 1988; Vizi and Elenkov, 2002). Instead, release of transmitter from postganglionic sympathetic axons occurs from specialized networks of varicosities from which neurotransmitters diffuse upwards of 1 μm before interacting with postjunctional receptors. It is estimated that this process generates NA concentrations of at least 500 nM within 10 μm of varicosities (Dunn et al., 1999). In addition to the release of NA from sympathetic varicosities, circulating catecholamines secreted by adrenal chromaffin cells may also influence immune cell responsiveness (Severn et al., 1992). Under normal resting conditions, plasma adrenaline and NA levels are approximately 30–100 pg/mL and 250 pg/mL, respectively (Esler et al., 1990). During periods of sympathetic activation, circulating catecholamine levels can be increased several fold. For example, during sepsis, plasma adrenaline and NA levels can reach as high as 4 ng/mL and 3.5 ng/mL, respectively (Zhou et al., 1992; Lin et al., 2005). 3. Neural regulation of innate and adaptive immunity The presence of noradrenergic varicosities within lymphoid tissues represents the anatomical substrate for sympathetic modulation of immunity. The immune response is mediated by antigen presenting cells (APCs), including macrophages and dendritic cells that are important cellular components of innate immunity, as well as helper T lymphocyte (Th) subsets that participate in the adaptive immune response (Elenkov et al., 2000; Sternberg, 2006; Iwasaki and Medzhitov, 2010). Cells involved in both innate and adaptive immunity bear functional β-ARs, though some cells, primarily monocytes and macrophages, also express α-ARs (Abrass et al., 1985; Sanders et al., 1997; Rosas-Ballina et al., 2011). NA can inhibit production and secretion of tumour necrosis factoralpha (TNFα) and interleukin (IL)-1β from macrophages harvested from the spleen and lymph nodes via β-AR signalling cascades (Ignatowski et al., 1996). These macrophage-derived products serve as both effector molecules, by killing dead/damaged cells for example, and paracrine signalling molecules, as they set the stage for engagement of the adaptive immune response (Wahl et al., 1975). The immunosuppressive effect of the sympathetic nervous system (SNS) on inflammatory cytokine release from macrophages has been confirmed by sympathetic denervation studies (Brown et al., 1991) and in vivo studies measuring splenic cytokine production following exposure to stress (Meltzer et al., 2004). While dampening pro-inflammatory cytokine production, β-AR signalling also potentiates release of antiinflammatory cytokines by APCs (van der Poll et al., 1996). However the effects of sympathetic neurotransmitters can differ depending on the AR subtype present on immune cells. NA signalling through α-ARs promotes TNFα release from macrophages (Bai et al., 2009). Additionally, activated immune cells can alter their expression of ARs, indicating plasticity of the immunomodulatory effects of the SNS during immune challenge (Martinolle et al., 1993). Th1 immune responses, which are defined on the basis of interferongamma (IFNγ), TNFα and IL-2 production, are generally inhibited following β-AR activation (Panina-Bordignon et al., 1997; Kin and Sanders, 2006), while NA fails to exert a direct effect on Th2 responsiveness (Nance and Sanders, 2007). Lack of β2-AR expression by Th2 cells likely provides the molecular substrate for the differential effects of SNS activity on Th1/Th2 functions (Sanders et al., 1997). However, through

suppression of Th1 immune signalling, NA relieves inhibition of Th2 cells and thus indirectly stimulates aspects of the Th2 immune response (Panina-Bordignon et al., 1997; Elenkov et al., 2000; Kin and Sanders, 2006). Recent findings also highlight the potential for an impact of AR stimulation on effector functions of Th17 lymphocytes, which are key in inflammatory bowel disease (IBD) pathogenesis (Duerr et al., 2006). β-AR activation was found to promote a Th17-polarizing phenotype by inducing production of IL-23, by APCs (Kim and Jones, 2010). Additionally, sympathectomy using a saporin-conjugated monoclonal antibody specific to dopamine β-hydroxylase reduced disease severity in mice with collagen-induced arthritis by down-regulating IL-17 release from CD4+ T cells (Harle et al., 2008). However, it currently remains to be seen whether NA is capable of stimulating IL-17 by direct actions on T lymphocytes or indirectly by inducing the release of cytokines that drive Th17 differentiation. In addition to catecholamines, evidence points to roles for the sympathetic co-transmitters, NPY and ATP, in immunomodulation. NPY influences both innate and adaptive immunity by actions on NPY receptors, namely the Y1 and Y5 subtypes, expressed by monocytes/ macrophages and lymphocytes (Petito et al., 1994; Bedoui et al., 2002; Dimitrijevic et al., 2002). In general, NPY signalling exerts antiinflammatory effects through the inhibition of pro-inflammatory cytokine release and activity of cellular mediators of the innate immune response (Irwin et al., 1991; Nair et al., 1993; Bedoui et al., 2003, 2008; Chandrasekharan et al., 2013). NPY also promotes Th2 cell responsiveness, similar to catecholamines, by suppressing Th1 cytokine release while simultaneously potentiating the release of Th2 differentiating cytokines. Furthermore, NPY can modulate the immunological properties of catecholamines released in lymphoid tissues. Co-administration of NPY and NA for example mitigated IL-6 release from splenic macrophages to a markedly greater extent than either transmitter administered alone (Straub et al., 2000). Similarly, purines co-released with sympathetic catecholamines can augment or suppress the inflammatory response depending on the receptor subtype activated (Eltzschig et al., 2013). Signalling to P2Y purinoceptors elicits the secretion of IL-10, a well-known suppressor of pro-inflammatory immune cell function, from macrophages (Bours et al., 2006; Kolachala et al., 2008; Roberts et al., 2012). Conversely, stimulation of P2X receptors on leukocytes exacerbates the inflammatory reaction by favouring the production of pro-inflammatory cytokines and inducing the inflammasome (Roberts et al., 2012; Eltzschig et al., 2013) Taken together, these findings support a role for the sympathetic catecholamines and cotransmitters in neuroimmune interactions. 4. The cholinergic anti-inflammatory pathway Recent evidence suggests that the SNS may also regulate GI inflammation through its participation in the cholinergic anti-inflammatory pathway. Over the past decade, stimulation of the vagus nerve has been shown to reduce inflammation in animal models of IBD and post-operative ileus (Ghia et al., 2007; The et al., 2007). Until recently, the motor pathway in this autonomic anti-inflammatory reflex was thought to be comprised entirely of parasympathetic neurons, due to the involvement of nicotinic receptors (Borovikova et al., 2000; Wang et al., 2003). However, studies using the endotoxemia model of systemic inflammation suggest that NA released by sympathetic varicosities within the spleen stimulates acetylcholine (ACh) release from a subset of splenic lymphocytes (Rosas-Ballina et al., 2008; Rosas-Ballina et al., 2011) plus Martinelle, McKinley and McAllen, this issue. It has since been shown that choline acetyltransferase (ChAT)expressing T lymphocytes suppress inflammation primarily by inhibiting leukocyte trafficking across vascular endothelium (Reardon et al., 2013), implicating a preferential role for cholinergic lymphocytes in the modulation of innate immune responses as opposed to adaptive immune responses. The generation of ChAT reporter mice has enhanced the ability to visualize cholinergic lymphocytes, and a recent analysis

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of ChAT expression in mouse GI tract confirms the existence of a sparse population of ChAT-expressing T-lymphocytes in the uninflamed GI tract (Gautron et al., 2013; Reardon et al., 2013). Although this suggests that they may be a target for the immunomodulatory effects of the sympathetic innervation, it remains to be seen what the relative contribution of ACh released from lymphocytes to GI immunomodulation is, compared to the large number of cholinergic nerve terminals of enteric neurons within the mucosa (see article by Sharkey and Savidge in this issue of Autonomic Neuroscience). Consistent with this, enteric neurons have been identified as the source of anti-inflammatory ACh release in a mouse model of post-operative ileus (Matteoli et al., 2013). 5. Sympathetic regulation of GI inflammation Evidence for sympathetic involvement in GI neuroimmune interactions originated from studies reporting a link between stress and clinical expression of GI inflammation (Brown, 1963; Kirkwood et al., 1983; Robertson et al., 1989). More recent evidence has emerged from work examining the effects of sympathectomy on disease progression in rodent models of colitis, as well as studies of the influence of selective AR agonists and antagonists on the inflammatory response during colitis, and is discussed below. The immunomodulatory effects of SNS signalling during GI inflammation vary depending upon the model of colitis. For example, chemical ablation of sympathetic nerves by 6-hydroxydopamine (6-OHDA) treatment in the trinitrobenzene sulphonic acid (TNBS) model of colitis in mice attenuated inflammation (McCafferty et al., 1997). Similarly, 6-OHDA treatment reduced disease severity in mice with dextran sulphate sodium (DSS)-induced acute colitis (Straub et al., 2008). In contrast, 6-OHDA increased disease severity in mice subjected to chronic DSS colitis. Sympathetic denervation also increased colitis severity in the IL-10 knockout mouse model of colitis (Straub et al., 2008). The discordant findings regarding the direction of sympathetic influence on GI inflammation likely reflect differences in experimental models used, time points at which sympathetic effects were examined following induction of colitis and rodent strain susceptibility to experimental inflammation. Nevertheless, these studies provide strong evidence for a role of the SNS in regulating intestinal inflammatory responses. Another approach to understanding immunomodulation by the SNS is to determine the effects of receptor-selective agonists on colitis severity. A β3-AR agonist dramatically reduced colon damage and inflammation in dinitrobenzene sulphonic acid (DNBS)-treated rats (Vasina et al., 2008). Agonists of the same receptor were also protective against the development of indomethacin-induced gastric ulcers (Kuratani et al., 1994; Sevak et al., 2002). However, β3-AR activation inhibits cholinergic-mediated contractions of the colon (Cellek et al., 2007), which might alter damage in models of chemically induced inflammation, and improves intramural blood flow (Kuratani et al., 1994), which may promote mucosal healing. Therefore, indirect effects could contribute to the protection from inflammation that is conferred by β3-AR signalling ((Vasina et al., 2008). Activation of β3-ARs by NA does however directly influence colonic cytokine release, leading to decreased secretion of the pro-inflammatory cytokine IL-6 from the colons of normal mice (Straub et al., 2006), which coincides with general views that β-ARs suppress the immune response and are antiinflammatory (Ursino et al., 2009). In contrast, α2-ARs appear to be pro-inflammatory in TNBS and DSS models of IBD in mice (Bai et al., 2009). Again, the modulation of inflammation by α2-ARs could be due to direct pro-inflammatory effects of activating α2-ARs on immune cells, or indirect effects due to α2-AR-mediated presynaptic inhibition of noradrenaline release. In conclusion, sympathetic modulation of GI inflammation likely involves a complex interplay between sympathetic neurons projecting to, and altering immune cell function, in addition to those primarily involved in motility, secretion, mucosal blood flow, and barrier function. Catecholamines can also impact the composition of the enteric

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microflora and its interactions with epithelial cells (Lyte et al., 2011) which is an important determinant of the level of immune activation within the gut. One way of distinguishing between the direct and indirect effects of AR activation on GI inflammation is through the use of bone marrow chimera mice. For example, receptor knockout bone marrow could be transplanted in irradiated mice that have functional ARs, meaning any effect of the receptor knockout may be ascribed to bone marrow-derived immune cells. This approach has recently been used to study AR signalling during endotoxemia (Walker-Brown and Roberts, 2009). Use of Cre-lox recombination to generate cell type-specific gene knockouts is another strategy that is likely to be fruitful in resolving the most important cell types and receptors involved in sympathetic immunomodulation. 6. Effects of gut inflammation on the SNS GI inflammation has widespread effects on the innervation of the gut, which likely contributes to symptom generation in patients with IBD. Striking morphological and functional changes in the ENS for example have been described during colitis in patients and animal models of IBD (Collins, 1996; Geboes and Collins, 1998; De Giorgio et al., 2004; Lomax et al., 2006). Loss of enteric neurons is a consistent histological feature of colitis. In addition, modifications in the neurochemical coding of enteric nerves and intrinsic properties of enteric neurons that affect their excitability and neurotransmission have been reported. GI inflammation can also alter ionic conductances in colonic nociceptive dorsal root ganglion (DRG) neurons, leading to increased neuronal excitability (Beyak and Vanner, 2005; Hughes et al., 2009), which may have implications for visceral pain in IBD. Patients with active ulcerative colitis (UC) exhibit an increase in the activity of the SNS as assessed by muscle sympathetic nerve recordings and spectral analysis of heart rate variability (Lechin et al., 1985; Furlan et al., 2006; Ganguli et al., 2007). Interestingly, treatment with clonidine, an agonist of α2-ARs, improved disease outcome in these patients. The mechanism of the anti-inflammatory effect of clonidine is thought to be due to its ability to presynaptically inhibit NA release from sympathetic varicosities, which suggests that elevated SNS activity may be pro-inflammatory in active UC. In addition to patients with active inflammation, those with IBD in clinical remission also exhibit markedly increased indices of sympathetic activity (Boisse et al., 2009; Sharma et al., 2009), suggesting that the effects of GI inflammation on sympathetic nerve dysfunction may persist in the absence of active disease. Intracellular electrophysiological recordings in vitro from the cell bodies of prevertebral ganglion neurons of guinea-pigs with TNBS-induced ileitis confirm the hyperactivity of postganglionic sympathetic neurons in response to GI inflammation (Dong et al., 2008). Despite hyperactivity of the SNS during IBD, NA levels in both the inflamed and uninflamed colonic mucosa are lower in patients with Crohn's disease (CD) than those serving as controls (Magro et al., 2002). Levels of circulating NA are unchanged in patients with UC which, in the context of enhanced sympathetic activity in these patients (Furlan et al., 2006), further suggests impaired SNS transmitter release in IBD. Our laboratory (Motagally et al., 2009b) and others (Swain et al., 1991; Jacobson et al., 1995, 1997) have reported that NA release is reduced during experimental colitis both in inflamed and uninflamed regions of the gut, further corroborating the findings of clinical studies. One weakness of these studies is that NA release was measured from tissues and not measured directly at release sites, so it is unclear if innervated cells are exposed to lower concentrations of NA during colitis, although this is assumed. There are several potential explanations that might reconcile increased postganglionic neuron activity with a decrease in NA release during colitis, such as a reduction in release sites due to neuroanatomical remodelling, as described in the following paragraphs. Another explanation may be that release from individual varicosities is impaired, despite increased neuronal excitability. Data from our laboratory suggest that colitis leads to inhibition of N-type

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voltage-gated Ca2+ current (ICa) in prevertebral sympathetic neurons, possibly due to the actions of TNFα (Motagally et al., 2009a,b). Since N-type channels are the predominant presynaptic Ca2 + channel responsible for excitation–secretion coupling in sympathetic varicosities (Wright and Angus, 1996), its inhibition during colitis may account for the drop in transmitter release despite heightened sympathetic activation. Interestingly, a similar reduction in ICa during colitis was observed in adrenal chromaffin cells (Lukewich and Lomax, 2011), suggesting that colitis may also reduce the adrenal secretion of catecholamines into the systemic circulation. Neuroanatomical plasticity of the sympathetic innervation of the gut in response to inflammation has been reported, although there is some variability with respect to whether inflammation enhances or reduces sympathetic axon density. Studies of mice with chronic DSS colitis reported a loss of sympathetic fibres in the serosal layer of the colon (Straub et al., 2005). A reduced number of sympathetic axons was also reported in all layers of surgically-resected tissues from CD patients (Dvorak and Silen, 1985; Straub, 2007). This is in contrast to the enhanced network of sympathetic axons demonstrated in rectal mucosal biopsy specimens from UC patients (Kyosola et al., 1977), and colonic lamina propria from acute DSS- and TNBS-treated mice (Bai et al., 2009). Furthermore, an increase in the density of sympathetic innervation of mesenteric blood vessels has been described in patients with CD and UC (Birch et al., 2008). A more than two-fold increase in catecholamine-containing sympathetic axons innervating the circular smooth muscle layer of the colon was also observed during TNBSinduced colitis in rats (Lourenssen et al., 2005). These discrepant findings likely reflect differences in the regions of the gut examined, the techniques used to identify or quantify sympathetic axons or the type, severity and duration of intestinal inflammation. Interestingly, a similar lack of consensus regarding the direction of sympathetic neuroanatomical change has emerged from studies of the innervation of inflamed joints (Miller et al., 2000; Ghilardi et al., 2012). 7. Concluding remarks The SNS and receptors for sympathetic neurotransmitters are capable of modulating GI inflammation. The major challenge facing the field at this time is determining whether sympathetic immunomodulation is the result of direct interactions with immune cells or indirect effects on parameters such as blood flow, barrier function and motility that can affect immune system activation. The development of this field is expected to result in the identification of the cell types and receptor subtypes most important for sympathetic immunomodulation, and in so doing yield new targets for suppression of pathological GI inflammation. Acknowledgments Work on this topic in the authors' laboratory was funded by the Crohn's and Colitis Foundation of Canada and the Canadian Institutes of Health Research. References Abrass, C.K., O'Connor, S.W., Scarpace, P.J., Abrass, I.B., 1985. Characterization of the betaadrenergic receptor of the rat peritoneal macrophage. J. Immunol. 135, 1338–1341. Bai, A., Lu, N., Guo, Y., Chen, J., Liu, Z., 2009. Modulation of inflammatory response via alpha2-adrenoceptor blockade in acute murine colitis. Clin. Exp. Immunol. 156, 353–362. Bedoui, S., Lechner, S., Gebhardt, T., Nave, H., Beck-Sickinger, A.G., Straub, R.H., Pabst, R., von HS, 2002. NPY modulates epinephrine-induced leukocytosis via Y-1 and Y-5 receptor activation in vivo: sympathetic co-transmission during leukocyte mobilization. J. Neuroimmunol. 132, 25–33. Bedoui, S., Miyake, S., Lin, Y., Miyamoto, K., Oki, S., Kawamura, N., Beck-Sickinger, A., von HS, Yamamura T, 2003. Neuropeptide Y (NPY) suppresses experimental autoimmune encephalomyelitis: NPY1 receptor-specific inhibition of autoreactive Th1 responses in vivo. J. Immunol. 171, 3451–3458.

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Neural regulation of gastrointestinal inflammation: role of the sympathetic nervous system.

The sympathetic innervation of the gastrointestinal (GI) tract regulates motility, secretion and blood flow by inhibiting the activity of the enteric ...
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