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Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility.

ABSTRACT: Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK:

SUBMITTER: Muller PA

PROVIDER: S-EPMC4149228 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility.

Muller Paul Andrew PA Koscsó Balázs B Rajani Gaurav Manohar GM Stevanovic Korey K Berres Marie-Luise ML Hashimoto Daigo D Mortha Arthur A Leboeuf Marylene M Li Xiu-Min XM Mucida Daniel D Stanley E Richard ER Dahan Stephanie S Margolis Kara Gross KG Gershon Michael David MD Merad Miriam M Bogunovic Milena M

Cell 20140701 2

Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogene ...[more]

PMID: 25036630

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Project description:Background & aimsWhen the glial fibrillary acidic protein (GFAP) promoter is used to express cellular toxins that eliminate glia in mice, intestinal epithelial permeability and proliferation increase; this led to the concept that glia are required for maintenance of the gastrointestinal epithelium. Many enteric glia, however, particularly in the mucosa, do not express GFAP. In contrast, virtually all enteric glia express proteolipid protein 1 (PLP1). We investigated whether elimination of PLP1-expressing cells compromises epithelial maintenance or gastrointestinal motility.MethodsWe generated mice that express tamoxifen-inducible Cre recombinase under control of the Plp1 promoter and carry the diptheria toxin subunit A (DTA) transgene in the Rosa26 locus (Plp1CreER;Rosa26DTA mice). In these mice, PLP1-expressing glia are selectively eliminated without affecting neighboring cells. We measured epithelial barrier function and gastrointestinal motility in these mice and littermate controls, and analyzed epithelial cell proliferation and ultrastructure from their intestinal tissues. To compare our findings with those from previous studies, we also eliminated glia with ganciclovir in GfapHSV-TK mice.ResultsExpression of DTA in PLP1-expressing cells selectively eliminated enteric glia from the small and large intestines, but caused no defects in epithelial proliferation, barrier integrity, or ultrastructure. In contrast, administration of ganciclovir to GfapHSV-TK mice eliminated fewer glia but caused considerable non-glial toxicity and epithelial cell death. Elimination of PLP1-expressing cells did not reduce survival of neurons in the intestine, but altered gastrointestinal motility in female, but not male, mice.ConclusionsUsing the Plp1 promoter to selectively eliminate glia in mice, we found that enteric glia are not required for maintenance of the intestinal epithelium, but are required for regulation of intestinal motility in females. Previous observations supporting the concept that maintenance of the intestinal epithelium requires enteric glia can be attributed to non-glial toxicity in GfapHSV-TK mice and epithelial-cell expression of GFAP. Contrary to widespread notions, enteric glia are therefore not required for epithelial homeostasis. However, they regulate intestinal motility in a sex-dependent manner.

Dataset Information

Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility.

Publications

Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility.

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