Role of visceral afferent neurons in mucosal inflammation and defense

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The maintenance of gastrointestinal (GI) mucosal integrity depends on the rapid alarm of protective mechanisms in the face of pending injury. Two populations of extrinsic primary afferent neurons, vagal and spinal, subserve this goal through different mechanisms. These sensory neurons react to GI insults by triggering protective autonomic reflexes including the so-called cholinergic anti-inflammatory reflex. Spinal afferents, in addition, can initiate protective tissue reactions at the site of assault through release of calcitonin gene-related peptide (CGRP) from their peripheral endings. The protective responses triggered by sensory neurons comprise alterations in GI blood flow, secretion, and motility as well as modifications of immune function. This article focusses on significant advances that during the past couple of years have been made in identifying molecular nocisensors on afferent neurons and in dissecting the signaling mechanisms whereby afferent neurons govern inflammatory processes in the gut.

Introduction

The physiological role of the gastrointestinal (GI) tract is not only to take up and digest food and absorb nutrients and water but also to sort out and eliminate harmful and useless material. These seemingly conflicting tasks require a molecular analysis of the luminal contents and the functional status of the GI tract, so that the appropriate effector programs can be selected [1]. To this end, the digestive system is endowed with an elaborate network of surveillance systems among which sensory neurons play a particular role. Thus, the gut is supplied by intrinsic sensory neurons of the enteric nerve plexuses as well as extrinsic spinal and vagal afferent neurons which are in close contact with two important non-neural surveillance systems in the mucosa: endocrine and immune cells [1]. With these connections and their sensory modalities, GI sensory neurons are able to recognize subtle changes in the chemical and physical environment within the lumen, interstitial space, vasculature, and muscle of the gut.

Sensory neurons subserve homeostasis and protection from adverse conditions through several mechanisms. These include firstly, sensations of pain, secondly, alterations in emotion, affect, and cognition, thirdly, induction of autonomic reflexes, fourthly, induction of neuroendocrine responses, and fifthly, initiation of protective tissue reactions at the site of assault (Figure 1). Within the gut, the protective mechanisms triggered by sensory neurons comprise alterations in blood flow, secretion and motility, and modifications of immune function. Work in the past decade has identified a phenomenal variety of molecular sensors that are expressed by primary afferent neurons and enable them to carry out their surveillance tasks [2]. This gain of knowledge has considerably advanced the understanding of both the physiology and pharmacology of afferent neurons in maintaining homeostasis of the GI mucosa in the face of challenge and injury. The current article highlights some of the most important advances that have been made in this field during the past two years.

Section snippets

Coordinated protection of the esophago-gastro-duodenal region

Despite its essential role in digestion, gastric acid is a constant threat to the integrity of the mucosa in the stomach and the adjacent esophageal and duodenal regions. Effective protection from the autoaggressive potential of acid is provided by mucosal defense mechanisms and appropriate compartmentalization of the esophago-gastro-duodenal region (Figure 2). The latter strategy is to prevent the escape of injurious concentrations of acid from the stomach, the mucosa of which is most

Spinal afferent nerve fibers as local emergency system in the GI mucosa

There is ample evidence that afferent neurons originating from the dorsal root ganglia participate in the local regulation of GI circulation, secretion, motility, mucosal homeostasis, and mucosal repair [1, 7, 8, 9, 10]. These tasks are accomplished by an efferent-like mode of operation: calcitonin gene-related peptide (CGRP) is released from the peripheral fibers of sensory neurons and, in turn, modifies the activity of several GI effector systems. It has not yet been ascertained whether the

Molecular acid sensors of afferent neurons involved in the protection of the gastro-duodenal mucosa

Most sensory neurons respond to extracellular acidosis. There is emerging evidence that the acid-sensitive ion channel TRPV1 (transient receptor potential vanilloid-1) plays a role in signaling for duodenal hyperemia in the face of luminal acidification [24••, 25]. TRPV1 is expressed by many afferent neurons innervating the rodent and human GI tract [26, 27, 28, 29, 30, 31, 32]. Since TRPV1 is located on sensory nerve terminals in the lamina propria behind the epithelium, the mucosal acid

Mucosal factors stimulating afferent neurons involved in gastric mucosal protection

Bradykinin, ghrelin, and melatonin have been identified as factors that facilitate GI mucosal protection through sensory neuron-dependent mechanisms. The effect of bradykinin to stimulate gastro-duodenal HCO3 secretion through an action involving sensory neurons is mediated by bradykinin B2 receptors and prostaglandin E2 [12•, 13]. Ghrelin is produced by endocrine cells of the gastric mucosa and known to excite vagal afferents which express ghrelin receptors [41]. The ability of this peptide

Proinflammatory effects mediated by sensory neurons in the gut

Despite the evidence that primary afferent neurons releasing CGRP contribute to GI mucosal defense, this functional implication must not be generalized because there is evidence that under certain conditions sensory neurons exacerbate inflammatory tissue reactions. For instance, gastritis induced by iodoacetamide or diquat is significantly reduced by capsaicin-induced ablation of sensory neurons [44] and colitis evoked by dextrane sulfate sodium is attenuated by TRPV1 blockers [45]. Likewise,

The vagal anti-inflammatory reflex

Cytokine-responsive vagal afferent neurons participate in the communication between the peripheral immune system and the brain [50, 51]. This function is supported by a particular proximity of vagal afferent nerve fibers to immunologically relevant structures such as hepatic Kupffer cells (macrophage-like cells), paraganglia, and connective tissue containing macrophages and dendritic cells [50, 51]. Bacterial lipopolysaccharide (endotoxin) is able to cause release of interleukin-1β from these

Conclusions

The role of primary afferent neurons in monitoring actual or potential threats to the GI mucosa is of physiological relevance to body homeostasis. Long thought to subserve primarily nociception, sensory neurons are now recognized to enforce GI mucosal defense through several mechanisms (Figure 1), among which autonomic reflexes and the initiation of protective tissue reactions at the site of insult play a particular role. Significant progress has been made in the past years to identify the

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Work in the author's laboratory was supported by the Zukunftsfonds Steiermark (grant 262) and the Austrian Scientific Research Funds (FWF grant L25-B05).

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