Neuroimmune signalling in the gut – mediators linked to disorders?

The enteric nervous system is certainly the most elaborated neural network of the body outside the central nervous system. It is involved in the regulation of functions as diverse as motility, secretion or nociception. In addition to housing such a complex network, the gut is also a privileged interface with environmental factors. In order to maintain homeostasis, a highly specialized enteric immune system has been developed as an efficient defence mechanism driving the eviction of noxious agents from the intestinal lumen. Activation of enteric immune system often leads to changes in enteric nervous system functions, as the two systems closely interact. Particularly, motor functions can be affected by neuroimmune mediators that are common to the two systems. Over the last decade, research has identified several immune mediators that are able to signal either directly or indirectly to the enteric nervous system, affecting motility functions. Those neuroimmune mediators which can be released from immune cells, but also epithelial cells, are thought to be responsible for motility disorders associated with inflammation or infection. Neuroimmune mediators affecting gut motility functions include cholecystokinin, histamine or proteases, but among those mediators, the lipid mediator prostaglandin E2 seems to occupy a place of choice. Prostaglandin E2 has been shown to cause changes in electrical properties of myenteric neurons, thereby potentially affecting gastrointestinal motility.1 However, recent studies have shown that prostaglandin E2 was also capable of direct activation of intestinal smooth cells, causing hypercontractility.2 In that study by Akiho et al., prostaglandin E2 was proposed to be responsible for persistent muscle hypercontractility observed after an infectious episode.2 More interestingly, this study showed that prostaglandin E2 release was the result of a post-infectious sustained expression of transforming growth factor beta-1 (TGF-β1), itself induced by the two T-helper-2 (Th2) cytokines interleukin-4 and interleukin-13. The authors showed that Th2 cytokines can induce muscle hypercontractility during infection, potentially by a direct activation of smooth muscle cells.2 Importantly, this study added cytokines to the list of immune mediators present in enteric neuromuscular tissues, and responsible for contractile changes in intestinal smooth muscles associated with postinfectious health status. Another study by the group of Ozaki reported in the present issue of Neurogastroenterology and Motility3 addresses even further the role of cytokines, and particularly pro-inflammatory cytokines in inflammation-associated motility disorders. Firstly, the authors nicely confirmed in a mouse animal model of colitis induced by the intracolonic administration of trinitrobenzene sulphonic acid (TNBS), that TNF-alpha (TNFα)-deficiency was beneficial, inhibiting the development of chronic inflammation. Next, they showed that TNFα-deficiency was not only inhibiting parameters of inflammation, but also significantly reduced inflammation-induced motility disorders. In TNFα-deficient mice, inflammation-induced inhibition of smooth muscle strip contractility in response to different mediators (KCl, carbachol, or L-type Ca2+ channels activators) was reversed compared with wild-type. Although these results show that the presence of TNFα has an impact on motility disorders associated with inflammation, it is impossible to define whether the effects of TNFα on gut motility are direct, or whether other inflammatory mediators reduced by the protective effects of TNFα deficiency on immune response, are involved in contractile dysfunctions. To address this issue, the authors have used organ culture system, where they exposed isolated longitudinal smooth muscle tissues from naïve mice, to TNFα for 3 days, thereby reproducing ex-vivo, the exposure of smooth muscle tissues to this pro-inflammatory cytokine. Under these conditions, longitudinal smooth muscle strips showed a decreased contractile response to carbachol, demonstrating that TNFα can directly modulate contractile functions of enteric smooth muscles, independently of its pro-inflammatory role. The possibility that TNFα exerts a direct effect on enteric smooth muscle cells is not addressed in the present paper, as only muscle strips and not isolated smooth muscle cells were used. Considering the work performed by Akiho et al. who showed direct effects of other cytokines on isolated enteric smooth muscle cells, similar hypothesis could be made for TNFα. However, we cannot rule out the possibility that TNFα might act on other resident cells associated with the longitudinal muscle strips, such as macrophages, mast cells or even myenteric neurons, which in turn could release mediators responsible for smooth muscle cell hypocontractility. Although direct signalling effect of TNFα on spinal afferents have been demonstrated, together with the expression of TNFα receptors on those neurons,4 no studies have yet reported the potential direct effects of TNFα on enteric neurons and/or potential consequences on motor functions. In contrast, other studies have well defined the effects of other two pro-inflammatory cytokines: interleukin-6 and interleukin-1, which act as excitatory neuromodulators of gastrointestinal motility through a direct action on myenteric neurons.5,6 Such effect for TNFα would have to be investigated in myenteric neurons. Another strength of the study by Ozaki's team is to report on a role for TNFα other than effects related to immune cell migration. By using the organ culture system, Kinoshita et al.3 showed that the effects of TNFα on induction of smooth muscle hypo-responsiveness are independent of the pro-inflammatory effects of TNFα related to leukocyte recruitment. This represents a step further in the comprehension of the mechanisms involved in the protective effects of anti-TNF therapies against inflammatory bowel disease-associated disorders. One important question is the source of inflammatory cytokines present in muscular layers of the gut upon inflammation. Studies have reported that smooth muscle cells can release cytokines such as interleukin-6,7 but resident macrophages are also likely sources of pro-inflammatory cytokines such as interleukin-1, interleukin-6 or TNFα. In the study by Kinoshita et al.3 the authors also report that interleukin-6 is present in higher amounts in muscular layers compared with mucosal layers. Since most of the infiltrated inflammatory cells are usually present in the lamina propria rather than in muscular layers, the high amount of interleukin-6 present in the muscle is most likely not released by infiltrated immune cells, but rather due to an intrinsic release of resident cells in the muscle layers. The source of TNFα present in muscle layers still has to be identified. The paper by Kinoshita et al.3 sheds light on a previously unexplored role for TNFα in the context of Inflammatory Bowel Disease, adding to our knowledge of the mechanisms responsible for the beneficial effects of anti-TNF therapies on gut dysfunctions associated with chronic inflammation. Cytokines, in general, and TNFα, in particular, need now to be regarded as yet another member of the neuroimmune mediator family involved in motility disorders.

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