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; Damian J 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:10.1126/sciadv.abd7954

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, Damian J 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 journal › Article (Academic Journal) › peer-review

76 Citations (Scopus)

Abstract

The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (T_regs), yet how the microbiota-T_reg cross-talk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E₂ (PGE₂), a well-known mediator of inflammation, inhibits mucosal T_regs in a manner depending on the gut microbiota. PGE₂ through its receptor EP4 diminishes T_reg-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 T_reg inhibition. Together, our findings provide emergent evidence that PGE₂-mediated disruption of microbiota-T_reg communication fosters intestinal inflammation.

Original language	English
Article number	eabd7954
Number of pages	16
Journal	Science Advances
Volume	7
Issue number	7
DOIs	https://doi.org/10.1126/sciadv.abd7954
Publication status	Published - 12 Feb 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.

Keywords

Dinoprostone/pharmacology
Gastrointestinal Microbiome
Humans
Inflammation
Receptors, Prostaglandin E, EP2 Subtype
T-Lymphocytes, Regulatory

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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. 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 = "Dinoprostone/pharmacology, Gastrointestinal Microbiome, Humans, Inflammation, Receptors, Prostaglandin E, EP2 Subtype, T-Lymphocytes, Regulatory",

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'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 Mole, \{Damian J\} and Konstantinos Gerasimidis and Schwarze, \{J{\"u}rgen K J\} and Breyer, \{Richard M\} and Arends, \{Mark J\} and O'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 = "Publisher Copyright: {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. ",

year = "2021",

month = feb,

day = "12",

doi = "10.1126/sciadv.abd7954",

language = "English",

volume = "7",

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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/10.1126/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, Damian J

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 - Dinoprostone/pharmacology

KW - Gastrointestinal Microbiome

KW - Humans

KW - Inflammation

KW - Receptors, Prostaglandin E, EP2 Subtype

KW - T-Lymphocytes, Regulatory

U2 - 10.1126/sciadv.abd7954

DO - 10.1126/sciadv.abd7954

M3 - Article (Academic Journal)

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

Bibliographical note

Keywords

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