Enteric glia promote visceral hypersensitivity during inflammation through intercellular signaling with gut nociceptors

Author:

Morales-Soto Wilmarie1ORCID,Gonzales Jacques1ORCID,Jackson William F.2,Gulbransen Brian D.1ORCID

Affiliation:

1. Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, MI 48824 USA.

2. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824 USA.

Abstract

Inflammation in the intestines causes abdominal pain that is challenging to manage. The terminals of sensory neurons innervating the gut are surrounded by glia. Here, using a mouse model of acute colitis, we found that enteric glia contribute to visceral pain by secreting factors that sensitized sensory nerves innervating the gut in response to inflammation. Acute colitis induced a transient increase in the production of proinflammatory cytokines in the intestines of male and female mice. Of these, IL-1β was produced in part by glia and augmented the opening of the intercellular communication hemichannel connexin-43 in glia, which made normally innocuous stimuli painful in female mice. Chemogenetic glial activation paired with calcium imaging in nerve terminals demonstrated that glia sensitized gut-innervating nociceptors only under inflammatory conditions. This inflammatory, glial-driven visceral hypersensitivity involved an increased abundance of the enzyme COX-2 in glia, resulting in greater production and release of prostaglandin E 2 that activated EP 4 receptors on sensory nerve terminals. Blocking EP 4 receptors reduced nociceptor sensitivity in response to glial stimulation in tissue samples from colitis-model mice, and impairing glial connexin-43 reduced visceral hypersensitivity induced by IL-1β in female mice. The findings suggest that therapies targeting enteric glial–neuron signaling might alleviate visceral pain caused by inflammatory disorders.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Cell Biology,Molecular Biology,Biochemistry

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