Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence

Abstract

Sensory neurons in the gastrointestinal tract have multi-faceted roles in maintaining homeostasis, detecting danger, and initiating protective responses. The gastrointestinal tract is innervated by three types of sensory neurons: dorsal root ganglia, nodose/jugular ganglia, and intrinsic primary afferent neurons. Here, we examine how these distinct sensory neurons and their signal transducers participate in regulating gastrointestinal inflammation and host defense. Sensory neurons are equipped with molecular sensors that enable neuronal detection of diverse environmental signals including thermal and mechanical stimuli, inflammatory mediators, and tissue damage. Emerging evidence shows that sensory neurons participate in host–microbe interactions. Sensory neurons are able to detect pathogenic and commensal bacteria through specific metabolites, cell-wall components, and toxins. Here we review recent work on the mechanisms of bacterial detection by distinct subtypes of gut-innervating sensory neurons. Upon activation, sensory neurons communicate to the immune system to modulate tissue inflammation through antidromic signaling and efferent neural circuits. We discuss how this neuro-immune regulation is orchestrated through transient receptor potential ion channels and sensory neuropeptides including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and pituitary adenylate cyclase-activating polypeptide. Recent studies also highlight a role for sensory neurons in regulating host defense against enteric bacterial pathogens including Salmonella typhimurium, Citrobacter rodentium, and enterotoxigenic Escherichia coli. Understanding how sensory neurons respond to gastrointestinal flora and communicate with immune cells to regulate host defense enhances our knowledge of host physiology and may form the basis for new approaches to treat gastrointestinal diseases.

Molecular and Functional Neuroscience in Immunity

“…In the spinal cord these neurons communicate with spinal interneurons, and relay neurons projecting to the brain (3) (Figure 2). A main group of these neurons, designated nociceptors, specialize in transmitting various forms of pain, which is also a cardinal feature of inflammation (3, 45, 46). The expression of several types of voltage-gated sodium channels, including Na v 1.7, Na v 1.8, and Na v 1.9, and transient receptor potential (TRP) ion channels, including TRPV1, TRPM8, and TRPA1, on sensory neurons mediates depolarization and specific thermal, mechanical, and chemical sensitivities to noxious stimuli (45, 47).…”

“…Sensory neurons, including nociceptors, also express receptors for cytokines, lipids, and growth factors (3). Cytokines, including TNF, IL-1β, IL-6, IL-17, prostaglandins, and other molecules released from macrophages, neutrophils, mast cells, and other immune cells in the vicinity, interact with sensory neurons through these receptors during infection, allergy, and tissue damage (46, 48–50) (Figure 2). These interactions result in an increased sensitivity of nociceptors to noxious stimuli, known as hyperalgesia, or in direct stimulation of sensory neurons (3, 45, 50).…”

“…These interactions result in an increased sensitivity of nociceptors to noxious stimuli, known as hyperalgesia, or in direct stimulation of sensory neurons (3, 45, 50). Commensal and pathogenic bacteria also activate sensory neurons through the release of specific metabolic molecules and toxins, acting on Na v 1.7, Na v 1.8, Na v 1.9, TRPV1, and TRPA1 (42, 46). …”

“…Some of these fibers, innervating the lungs, airways, and other organs, express TRPV1, TRPA1, Na v 1.7, Na v 1.8, and Na v 1.9 and function as nociceptors (19, 51, 52). Vagal sensory neurons are activated during bacterial or viral infection, cellular damage, and airway allergenic responses (19, 44, 46, 53, 54). This activation is mediated by TNF, IL-1β, prostaglandins, serotonin, and other molecules released from immune cells, including neutrophils, macrophages, and eosinophils (19, 44).…”

“…In addition to sensing immune molecules and pathogens, afferent neurons actively modulate immune responses and inflammation, as demonstrated in experimental IBD (46), arthritis (48), asthma (60), skin inflammation and chronic itch (61, 62), and bacterial infection (3, 42). Sensory neurons release substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and other molecules interacting with the endothelium, neutrophils, macrophages, and other immune cells in the vicinity of axonal terminals (3, 42, 63) (Figure 2).…”