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• W2037636746 abstract "Activated immune cells, such as mast cells, trigger sensory neuron fibers via local release of inflammatory mediators (1). Dual neuro-immune interactions are illustrated by the expression of receptors for immune cell derived mediators, like for instance tryptase, histamine, TNF, or interleukin 1β, by afferent nerves (2). Mutual associations between nerves and mast cells have been described in normal and pathological conditions, such as in irritable bowel syndrome, atopic dermatitis, and interstitial cystitis (1). On the other hand, the nervous system regulates immune function and inflammation. In a series of recent papers, evidence has accumulated for an important role of the autonomic nervous system in regulating the communication between the brain and the (visceral) immune system, illustrating the ability of the brain to reflexively control immune activation in response to excessive acute inflammation (3,4). We will focus on the involvement of the autonomic nervous system in regulating inflammation, in particular that of the vagal nerve. We will update advances in the recently discovered anti-inflammatory role of the efferent vagal nerve and its implications on the treatment of inflammatory conditions that impair intestinal motility, such as in postoperative ileus. Intestinal macrophage activation and cytokine release is a common hallmark of acute gut inflammation, observed after intestinal manipulation, bowel transplantation, or ischemia/reperfusion injury. These kinds of inflammatory stimuli trigger vagal afferents that signal from visceral sites to brain nuclei, and activate a reflex response that ultimately leads to efferent vagal nerve signaling (5). Efferent activity of the vagus nerve releases acetylcholine in the vicinity of peripheral macrophages at nanomolar quantities. Depending on the subtype and anatomic location, macrophages express nicotinic acetylcholine receptors (nAchRs) (4,6). Specifically, nicotinic activation of the specific subtype of nAChRs consisting of α7 subunits has been shown to lead to cellular deactivation and inhibition of cytokine release, in macrophages activated by exposure to bacterial products. This phenomenon has been termed the ‘cholinergic anti-inflammatory pathway’ and has first been substantiated by Borokova et al in 2000 in a murine model for sepsis. This was the first of a series of breakthrough papers, in which this direct connection between the nervous and immune system was employed therapeutically in animal models of inflammatory sepsis, via direct electrical stimulation of the vagal nerve, or through the use of cholinergic agonists that specifically activate the macrophage α7 subunit of the nAChR. The cholinergic anti-inflammatory pathway has turned out to be a physiological neural system of reflexively monitoring and adjusting the inflammatory response by inhibiting pro-inflammatory cytokine synthesis. In particular, macrophage activation is subject to cholinergic regulation, and vagal nerve stimulation has been shown to inhibit the release of a wide array of macrophage inflammatory mediators such as TNF, HMGB1, IL6, MIP1α and β, MIP2, and IL18. In this light, our laboratory has focused on the novel treatment strategies for postoperative ileus (POI), a commonly accepted pathological state in which acute inflammatory responses in the bowel wall, induced by gut manipulation during surgery, impair postoperative gut motility. Post-operative ileus (POI) is an inevitable outcome of essentially every abdominal surgical procedure, and typical clinical signs include bowel distension, nausea, and vomiting, causing considerable discomfort. Clinically, treatment of ileus concentrates on symptomatic relief with nasogastric suction, or reduction of the peripheral effect of μ-opioids that are known to intensify ileus. We have previously developed a murine model to study inflammatory and GI-motility responses to surgical intestinal manipulation (7). Previous studies have suggested that the pathogenesis of POI may involve activation of intestinal macrophages in the intestine due to manipulation during surgical procedures. Earlier studies have revealed the presence of an intriguing network of resident macrophages residing in the muscularis externa of the small intestine (8). These cells were found to express macrophage-specific membrane markers, and are immuno-competent with respect to phagocytosis and immune activation. Importantly, following intestinal surgery these normally quiescent macrophages are able to up-regulate expression of cytokines and integrins required to initiate tissue inflammation and to recruit inflammatory cells from the blood stream. In our murine model, we recently discovered that intestinal manipulation results in a rapid up-regulation of the expression of MHC II and LFA-1 in resident macrophages, indicative of their activation. This observation points towards a potentially important role for these cells in initiating the muscular immune response that mediates POI. Similarly, the activation of macrophages following bowel manipulation has been demonstrated in rat and human small intestinal muscularis externa (9). Once activated, these cells release pro-inflammatory mediators leading to inflammation of the bowel wall and inhibition of the contractile properties of rodent, and human manipulated intestine. Motility of gastrointestinal segments distant from the site of manipulation is also inhibited by the locally induced inflammation, which demonstrates that POI is the result of (inflammatory) activation of inhibitory neural pathways that elicits paralysis of the entire GI-tract (7). This neuro-immune interaction was illustrated not only functionally, but also by histological staining of the early response gene cfos in spinal nuclei, indicating activation of spinal sensory nerves triggered by inflammation of the muscularis externa of manipulated intestine (7). Recently, we have provided evidence that cholinergic efferent activation can inhibit activation of macrophages by intestinal manipulation in our model for POI (10). We found that the muscular inflammation and POI normally induced by bowel manipulation is attenuated by peri-operative stimulation of the left cervical vagal nerve. Further results in vivo, and in vitro, confirm that α7 nAchR activation by nicotine blunts the production of TNF, IL-1β, IL-6, MIP1α and MIP2, but not IL-10 after challenge with endotoxin. Hence, the activation of the efferent vagal nerve leads to modulation of macrophage activation and inflammation by activating nAchRs present on peritoneal macrophages. Over the past years, the cholinergic anti-inflammatory pathway is increasingly recognized as a ‘hard-wired’ physiological mechanism to rapidly respond to- and regulate acute immune responses by the CNS (5). In animal models, enhancing the activity of this pathway by means of electrical stimulation of the vagal nerve, or the use of cholinergic agents, has indicated that this pathway can be modulated for therapeutic use. However, the subcellular mechanism behind the de-activating action of acetylcholine on macrophage function has remained largely unknown. With respect to the latter, experiments in our laboratory have demonstrated the requirement of two transcription factors in the cholinergic anti-inflammatory response: Signal Transducer and Activator of Transcription-3 (Stat-3) and its downstream gene Suppressor of Cytokine Signaling-3 (Socs-3). We were able to demonstrate that α7 nAchR activation in macrophages induced activation of Stat-3 and inhibited pro-inflammatory cytokine release in vitro as well as in vivo. These data demonstrate that nicotine exerts its anti-inflammatory action by activating Stat-3/Socs-3 signaling cascade via the α7 nicotinic acetylcholine receptor. Intriguingly, subsequent immunoprecipitation experiments performed at our laboratory strongly indicate that nAchR activation induces recruitment of tyrosine kinase Janus Kinase-2-that phosphorylates Stat-3- to the receptor. This finding attributes a novel function to the α7 nAchR in macrophages in regulating inflammatory responses, in addition to its long established function as a neuronal ion channel. Noteworthy, Stat-3/Socs-3 signaling factors have previously been established as essential for the anti-inflammatory action of interleukin 10. Hence, this nAchR signaling route would perfectly explain the anti-inflammatory properties of nicotine, as Stat-3/Socs-3 signaling is a negative regulatory pathway of immune responses. Our current research focuses on further elucidation of the molecular pathways that are involved in the modulation of macrophage activation by vagal nerve activity. Detailed knowledge on the subtype of nAchRs, and the downstream mechanism involved is required to define drug targets to pharmacologically modulate the cholinergic anti-inflammatory pathway for therapeutic use." @default.
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• W2037636746 title "Inflammation and Gut Motility; Neural Control of Intestinal Immune Cell Activation" @default.
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• W2037636746 doi "https://doi.org/10.1097/01.scs.0000180287.58988.86" @default.
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