Modulation of the immune response by helminths: a role for serotonin?

Abstract

The mammalian gut is a remarkable organ: with a nervous system that rivals the spinal cord, it is the body's largest repository of immune and endocrine cells and houses an immense and complex microbiota. Infection with helminth parasites elicits a conserved program of effector and regulatory immune responses to eradicate the worm, limit tissue damage, and return the gut to homeostasis. Discrete changes in the nervous system, and to a lesser extent the enteroendocrine system, occur following helminth infection but the importance of these adaptations in expelling the worm is poorly understood. Approximately 90% of the body's serotonin (5-hydroxytryptamine (5-HT)) is made in enterochromaffin (EC) cells in the gut, indicative of the importance of this amine in intestinal function. Signaling via a plethora of receptor subtypes, substantial evidence illustrates that 5-HT affects immunity. A small number of studies document changes in 5-HT levels following infection with helminth parasites, but these have not been complemented by an understanding of the role of 5-HT in the host-parasite interaction. In reviewing this area, the gap in knowledge of how changes in the enteric serotonergic system affects the outcome of infection with intestinal helminths is apparent. We present this as a call-to-action by investigators in the field. We contend that neuronal EC cell-immune interactions in the gut are essential in maintaining homeostasis and, when perturbed, contribute to pathophysiology. The full affect of infection with helminth parasites needs to define, and then mechanistically dissect the role of the enteric nervous and enteroendocrine systems of the gut.

Keywords: enterochromaffin cell; helminth; intestine; serotonin.

Figure 1. Synthesis and degradation of serotonin in EC cells

Serotonin (5-HT) is synthesized by EC cells (purple) in the GI tract from l-tryptophan via the rate-limiting enzyme TPH-1. l-5-hydroxytryptophan is then converted into active 5-HT by l-aromatic acid decarboxylase (AADC) and stored in EC granules. Apically, EC cells are stimulated to secrete 5-HT by G-protein coupled receptors (GPCR) in the colon and by glucose-dependent insulinotropic peptide-1 (GLP)-1 in the small intestine, while 5-HT₄R inhibits 5-HT release. Basolaterally, EC cells express muscarinic, adrenergic, and 5-HT₃ receptors, activation of which leads to 5-HT release, while activation of GABA_A, nicotinic, somatostatin-R₂, and 5-HT₄R inhibit 5-HT release. EC cells or enterocytes (orange) can uptake 5-HT via the serotonin reuptake transporter (SERT) and degrade 5-HT to 5-hydroxindole acetic acid via enzyme monoamine oxidase (MAO) (R, receptors).

Figure 2. The potential for serotonin to influence the immune response against infection with helminth parasites

The Th2 response following infection with helminths begins when the parasite is recognized by the epithelium (enterocyte, EC cell, or tuft cell) and/or antigen-presenting cells such as the DC or macrophages. Tuft cells release IL-25 and activate innate lymphoid type 2 cells (ILC2s). ILC2s, along with activated DCs, promote the differentiation and proliferation of naïve CD4⁺ T cells into Th2 effector cells by the release of IL-13, and then IL-4, IL-10, and TGFβ, respectively. Th2 cells subsequently secrete Th2 cytokines (IL-4, IL-5, IL-9, and IL-13) leading to responses directed at worm expulsion, such as goblet cell hyperplasia. Serotonin released by cells contributes to the ‘washer-sweeper’ response via goblet cell hyperplasia and mucin exocytosis, and increased GI peristalsis through its actions on enteric neurones and smooth muscle. The expression of serotonin receptors on the many components of the mucosal immune system suggest that 5-HT likely plays, at least, a modulatory role in the hosts’ anti-worm response.

Figure 3. Simplified schema showing how infection with a parasitic helminth can affect serotonergic signaling to influence overall health (red boxes), and how this can be modified or mediated by the gut microbiota and integrated into a common theme of neuro-immunity