Journal Article

Regulation of intestinal immunity and tissue repair by enteric glia

Shapiro, Michael, Stockinger, Brigitta, Progatzky, Fränze, Garcia-Cassani, Bethania, Boeing, Stefan, Rahim, Maryam, Shah, Kathleen, Pachnis, Vassilis, Lasrado, Reena, Chng, Song Hui, Entwistle, Lewis J., Amaniti, Eleni-Maria, Laddach, Anna, Wilson, Mark S., Classon, Cajsa Helena, Sevgi, Selin, Bon-Frauches, Ana Carina, Suárez-Bonnet, Alejandro

2021

Overview

Tissue maintenance and repair depend on the integrated activity of multiple cell types 1 . Whereas the contributions of epithelial 2 , 3 , immune 4 , 5 and stromal cells 6 , 7 in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease 8 . Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ–EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ–EGC–CXCL10 axis in immune response and tissue repair after infectious challenge. Enteric glial cells have tissue-wide immunoregulatory roles through the upregulation of IFNγ-dependent genes both at steady state and after parasite infection, promoting immune homeostasis and CXCL10-mediated tissue repair after pathogen-induced intestinal damage in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/31 / 13/51 / 14/19 / 14/32 / 14/63 / 38/77 / 38/91 / 631/250/255/1715 / 631/378/2596 / 64/60 / Adventitia - immunology / Adventitia - parasitology / Animals / Cell cycle / Chemokine CXCL10 - immunology / Chemokines / Colon / CXCL10 protein / Duodenum - immunology / Duodenum - parasitology / Duodenum - pathology / Duodenum - physiology / Female / Fibroblasts / Gene expression / Glia / Glial cells / Gliosis / Homeostasis / Homeostasis - immunology / Humanities and Social Sciences / Humans / Immune response / Immune system / Immunity / Infections / Inflammation - immunology / Inflammation - pathology / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory response / Interferon / Interferon-gamma - immunology / Intestine / Intestines - immunology / Intestines - parasitology / Intestines - pathology / Intestines - physiology / Male / Mice / multidisciplinary / Nematospiroides dubius - immunology / Nematospiroides dubius - pathogenicity / Neuroglia / Neuroglia - immunology / Neuroglia - physiology / Pathology / Regeneration / Repair / Repair & maintenance / Roles / Science / Science (multidisciplinary) / Signal Transduction - immunology / Signaling / Smooth muscle / Strongylida Infections - immunology / Strongylida Infections - parasitology / Strongylida Infections - pathology / Tissue engineering / Tissues / Transcription activation / Transcriptomics / γ-Interferon