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 Mole; Konstantinos 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

doi:10.1101/2020.07.12.199513

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 Mole

Konstantinos 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

Veterinary Services

Research output: Contribution to journal › Article › peer-review

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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 language	English
Article number	eabd7954
Number of pages	16
Journal	Science advances
Volume	7
Issue number	7
Early online date	12 Feb 2021
DOIs	https://doi.org/10.1101/2020.07.12.199513 https://doi.org/10.1126/sciadv.abd7954
Publication status	First published - 12 Feb 2021

Bibliographical note

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

Keywords

immunology

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10.1126/sciadv.abd7954Licence: CC BY

eabd7954.fullFinal published version, 10.1 MBLicence: CC BY

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Crittenden, S., Goepp, M., Pollock, J., Robb, C. T., Smyth, D. J., Zhou, Y., Andrews, R., Tyrrell, V., Gkikas, K., Adima, A., O’Connor, R. A., Davies, L., Li, X.-F., Yao, H. X., Ho, G.-T., Zheng, X., Mair, A., Vermeren, S., Qian, B.-Z., ... Yao, C. (2021). Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells. Science advances, 7(7), Article eabd7954. Advance online publication. https://doi.org/10.1101/2020.07.12.199513, https://doi.org/10.1126/sciadv.abd7954

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title = "Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells",

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.",

keywords = "immunology",

author = "Siobhan Crittenden and Marie Goepp and Jolinda Pollock and Robb, \{Calum T\} and Smyth, \{Danielle J.\} and You Zhou and Robert Andrews and Victoria Tyrrell and Konstantinos Gkikas and Alexander Adima and O{\textquoteright}Connor, \{Richard A.\} and Luke Davies and Xue-Feng Li and Yao, \{Hatti X\} and Gwo-Tzer Ho and Xiaozhong Zheng and Amil Mair and Sonja Vermeren and Bin-Zhi Qian and DJ Mole and Konstantinos Gerasimidis and Schwarze, \{J{\"u}rgen K.J.\} and Breyer, \{Richard M\} and Arends, \{Mark J\} and O{\textquoteright}Donnell, \{Valerie B.\} and Iredale, \{John P\} and Anderton, \{Stephen M.\} and Shuh Narumiya and Maizels, \{Rick M.\} and Rossi, \{Adriano G\} and Howie, \{Sarah E\} and Chengcan Yao",

note = "Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).",

year = "2021",

month = feb,

day = "12",

doi = "10.1101/2020.07.12.199513",

language = "English",

volume = "7",

journal = "Science advances",

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Crittenden, S, Goepp, M, Pollock, J, Robb, CT, Smyth, DJ, Zhou, Y, Andrews, R, Tyrrell, V, Gkikas, K, Adima, A, O’Connor, RA, Davies, L, Li, X-F, Yao, HX, Ho, G-T, Zheng, X, Mair, A, Vermeren, S, Qian, B-Z, Mole, DJ, Gerasimidis, K, Schwarze, JKJ, Breyer, RM, Arends, MJ, O’Donnell, VB, Iredale, JP, Anderton, SM, Narumiya, S, Maizels, RM, Rossi, AG, Howie, SE & Yao, C 2021, 'Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells', Science advances, vol. 7, no. 7, eabd7954. https://doi.org/10.1101/2020.07.12.199513, https://doi.org/10.1126/sciadv.abd7954

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

N1 - Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

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 - https://www.scopus.com/pages/publications/85100967260

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 -

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

Abstract

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Keywords

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