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

Siobhan Crittenden, Marie Goepp, Jolinda Pollock, Calum T Robb, Danielle J. Smyth, You Zhou, Robert Andrews, Victoria Tyrrell, Konstantinos Gkikas, Alexander Adima, Richard A. O’Connor, Luke Davies, Xue-Feng Li, Hatti X Yao, Gwo-Tzer Ho, Xiaozhong Zheng, Amil Mair, Sonja Vermeren, Bin-Zhi Qian, DJ MoleKonstantinos Gerasimidis, Jürgen K.J. Schwarze, Richard M Breyer, Mark J Arends, Valerie B. O’Donnell, John P Iredale, Stephen M. Anderton, Shuh Narumiya, Rick M. Maizels, Adriano G Rossi, Sarah E Howie, Chengcan Yao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
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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.
Original languageEnglish
Article numbereabd7954
Number of pages16
JournalScience advances
Volume7
Issue number7
Early online date12 Feb 2021
DOIs
Publication statusFirst published - 12 Feb 2021

Keywords

  • immunology

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