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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, 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., 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: 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: 18 Feb 2021 13:30
URI: http://orca.cf.ac.uk/id/eprint/138622

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