TY - JOUR
T1 - Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells
AU - Crittenden, Siobhan
AU - Goepp, Marie
AU - Pollock, Jolinda
AU - Robb, Calum T
AU - Smyth, Danielle J.
AU - Zhou, You
AU - Andrews, Robert
AU - Tyrrell, Victoria
AU - Gkikas, Konstantinos
AU - Adima, Alexander
AU - O’Connor, Richard A.
AU - Davies, Luke
AU - Li, Xue-Feng
AU - Yao, Hatti X
AU - Ho, Gwo-Tzer
AU - Zheng, Xiaozhong
AU - Mair, Amil
AU - Vermeren, Sonja
AU - Qian, Bin-Zhi
AU - Mole, DJ
AU - Gerasimidis, Konstantinos
AU - Schwarze, Jürgen K.J.
AU - Breyer, Richard M
AU - Arends, Mark J
AU - O’Donnell, Valerie B.
AU - Iredale, John P
AU - Anderton, Stephen M.
AU - Narumiya, Shuh
AU - Maizels, Rick M.
AU - Rossi, Adriano G
AU - Howie, Sarah E
AU - Yao, Chengcan
PY - 2021/2/12
Y1 - 2021/2/12
N2 - 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.
AB - 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.
KW - immunology
UR - https://advances.sciencemag.org/content/suppl/2021/02/08/7.7.eabd7954.DC1
UR - http://www.scopus.com/inward/record.url?scp=85100967260&partnerID=8YFLogxK
U2 - 10.1101/2020.07.12.199513
DO - 10.1101/2020.07.12.199513
M3 - Article
C2 - 33579710
SN - 2375-2548
VL - 7
JO - Science advances
JF - Science advances
IS - 7
M1 - eabd7954
ER -