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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:, 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:, 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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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: 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: 04 May 2023 02:06

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