Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells

Crittenden, Siobhan, Goepp, Marie, Pollock, Jolinda, Robb, Calum T., Smyth, Danielle J., Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291, Andrews, Robert, Tyrrell, Victoria, Gkikas, Konstantinos, Adima, Alexander, O'Connor, Richard A., Davies, Luke, Li, Xue-Feng, Yao, Hatti X., Ho, Gwo-Tzer, Zheng, Xiaozhong, Mair, Amil, Vermeren, Sonja, Qian, Bin-Zhi, Mole, Damian J., Gerasimidis, Konstantinos, Schwarze, Jürgen K. J., Breyer, Richard M., Arends, Mark J., O'Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460, Iredale, John P., Anderton, Stephen M., Narumiya, Shuh, Maizels, Rick M., Rossi, Adriano G., Howie, Sarah E. and Yao, Chengcan 2021. Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells. Science Advances 7 (7) , eabd7954. 10.1126/sciadv.abd7954

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Abstract

The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (Tregs), yet how the microbiota-Treg cross-talk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E2 (PGE2), a well-known mediator of inflammation, inhibits mucosal Tregs in a manner depending on the gut microbiota. PGE2 through its receptor EP4 diminishes Treg-favorable commensal microbiota. Transfer of the gut microbiota that was modified by PGE2-EP4 signaling modulates mucosal Treg responses and exacerbates intestinal inflammation. Mechanistically, PGE2-modified microbiota regulates intestinal mononuclear phagocytes and type I interferon signaling. Depletion of mononuclear phagocytes or deficiency of type I interferon receptor diminishes PGE2-dependent Treg inhibition. Together, our findings provide emergent evidence that PGE2-mediated disruption of microbiota-Treg communication fosters intestinal inflammation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Medicine Systems Immunity Research Institute (SIURI)
Publisher:	American Association for the Advancement of Science
ISSN:	2375-2548
Date of First Compliant Deposit:	18 February 2021
Date of Acceptance:	24 December 2020
Last Modified:	24 Jul 2024 15:05
URI:	https://orca.cardiff.ac.uk/id/eprint/138622

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