Interleukin-33 promotes seratonin release from enterochromaffin cells for intestional homeostasis

Authors: CHEN, ZUOJIA - National Cancer Institute (NCI, NIH); LUO, JIALIE - National Cancer Institute (NCI, NIH); LI, JIAN - National Cancer Institute (NCI, NIH); KIM, GIRAK - National Cancer Institute (NCI, NIH); STEWART, ANDY - National Cancer Institute (NCI, NIH); Urban, Joseph; HUANG, YUEFENG - National Cancer Institute (NCI, NIH); CHEN, SHAN - National Institutes Of Health (NIH); WU, LING-GANG - National Institutes Of Health (NIH); CHESTER, ALEXANDER - National Institutes Of Health (NIH); TRINCHIERI, GIORGIO - National Cancer Institute (NCI, NIH); LI, WEI - National Institutes Of Health (NIH); WU, CHUAN - National Cancer Institute (NCI, NIH)

Submitted to: Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/20/2020
Publication Date: 11/20/2020
Citation: Chen, Z., Luo, J., Li, J., Kim, G., Stewart, A., Urban Jr, J.F., Huang, Y., Chen, S., Wu, L., Chester, A., Trinchieri, G., Li, W., Wu, C. 2020. Interleukin-33 promotes seratonin release from enterochromaffin cells for intestional homeostasis. Immunity. 54(1):151-163.e6. https://doi.org/doi:10.1016/j.immuni.2020.10.014.
DOI: https://doi.org/10.1016/j.immuni.2020.10.014

Interpretive Summary: Parasitic nematodes (worms) that infect agricultural animals reduce the production of meat, milk and fiber, and those that infect humans compromise health and well-being due to increased morbidity and reduced quality of life. They can also be used when infecting the gastrointestinal track to incite the host mechanism of protection that also effects gut physiology and indicates mechanisms that reveal control over intestinal function. By utilizing a mousemodel of intestinal worm infection with the common whip worm, an unexpected role for a host protein called IL-33 was found to induce instantaneous peristaltic movement that facilitated intestinal worm expulsion from the intestine. In addition, through studies of secretory processes, cell imaging, use of special genetically altered knockout mice and single cell electrophysiology, it was found that IL-33 signaling through a cell receptor specifically regulated the rapid release of the signaling molecule serotonin or 5-HT which influences gut motility. These findings established a novel mechanism that rapidly converts IL-33 that is induced by immune stimulation of intestinal cells into the release of 5-HT that triggers motility bridging the intestinal immune system, nervous system and endocrine system to regulate intestinal homeostasis and host defense against intestinal infection. This information is important to those interested in novel drug development to control parasitic infection in livestock and humans in order to enhance their health and well-being in a cost-effective and practical way, and to understand how diet can modulate responses to infection and enhance intestinal health.

Technical Abstract: Coordination between immune and neuroendocrine systems is critical for homeostasis of the gastrointestinal (GI) tract. Enterochromaffin (EC) cells as chemosensors are largely involved in GI physiology and pathophysiology, such as gut motility and host defense by quickly responding to environmental cues and releasing serotonin (5-hydroxytrypramine, 5-HT). However, how immune factors participate in such a rapid release of 5-HT by EC cells remains unclear. We observed an unexpected role of the alarmin cytokine IL-33 in regulating 5-HT release directly from EC cells via the IL-33 receptor ST2. Loss of IL-33-ST2 signaling in EC cells resulted in reduction of peripheral 5-HT release, leading to impaired intestinal peristalsis and helminth clearance. Mechanistically, we demonstrated that IL-33-ST2 signaling activated the transient receptor potential A1 (TRPA1) channel on EC cells via intracellular Ca2+, leading to 5-HT release. Our data provide novel cellular and molecular mechanisms of the immune-neuroendocrine axis in rapidly calibrating 5-HT release from EC cells.