Regulation of intestinal immunity and tissue repair by enteric glia

Fränze Progatzky (), Michael Shapiro, Song Hui Chng, Bethania Garcia-Cassani, Cajsa Helena Classon, Selin Sevgi, Anna Laddach, Ana Carina Bon-Frauches, Reena Lasrado, Maryam Rahim, Eleni-Maria Amaniti, Stefan Boeing, Kathleen Shah, Lewis J. Entwistle, Alejandro Suárez-Bonnet, Mark S. Wilson, Brigitta Stockinger and Vassilis Pachnis ()
Additional contact information
Fränze Progatzky: The Francis Crick Institute
Michael Shapiro: The Francis Crick Institute
Song Hui Chng: The Francis Crick Institute
Bethania Garcia-Cassani: The Francis Crick Institute
Cajsa Helena Classon: The Francis Crick Institute
Selin Sevgi: The Francis Crick Institute
Anna Laddach: The Francis Crick Institute
Ana Carina Bon-Frauches: The Francis Crick Institute
Reena Lasrado: The Francis Crick Institute
Maryam Rahim: The Francis Crick Institute
Eleni-Maria Amaniti: The Francis Crick Institute
Stefan Boeing: The Francis Crick Institute
Kathleen Shah: The Francis Crick Institute
Lewis J. Entwistle: The Francis Crick Institute
Alejandro Suárez-Bonnet: The Royal Veterinary College
Mark S. Wilson: Genentech Inc
Brigitta Stockinger: The Francis Crick Institute
Vassilis Pachnis: The Francis Crick Institute

Nature, 2021, vol. 599, issue 7883, 125-130

Abstract: Abstract Tissue maintenance and repair depend on the integrated activity of multiple cell types1. Whereas the contributions of epithelial2,3, immune4,5 and stromal cells6,7 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 disease8. 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.

Date: 2021
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DOI: 10.1038/s41586-021-04006-z

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