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

Siobhan Crittenden; Marie Goepp; Jolinda Pollock; Calum 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 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 M 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 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 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 M Howie, Chengcan Yao

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

Abstract / Description of output

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 crosstalk 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. Taken together, our findings provide emergent evidence that PGE2-mediated disruption of microbiota-Treg communication fosters intestinal inflammation

Original language	English
Journal	Science Advances
DOIs	https://doi.org/10.1126/sciadv.abd7954
Publication status	Published - 12 Feb 2021

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Investigating the immune mechanisms underlying NSAID chemoprevention of colorectal cancer
Yao, C.
UK-based charities
1/08/18 → 31/01/22
Project: Research
To delineate immune mechanisms for limiting asthma development and severity
Yao, C.
MRC
1/02/18 → 31/01/23
Project: Research

Institute for Regeneration and Repair Flow Cytometry Facility
Shonna Johnston (Manager), Fiona Rossi (Manager), Claire Cryer (Other) & Ailsa Laird (Other)
Institute of Regeneration and Repair
Facility/equipment: Facility

Cite this

Crittenden, S., Goepp, M., Pollock, J., Robb, C., 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. https://doi.org/10.1126/sciadv.abd7954

@article{9c7a671f78f14ccb82ec5b3c075c0191,

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 crosstalk 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. Taken together, our findings provide emergent evidence that PGE2-mediated disruption of microbiota-Treg communication fosters intestinal inflammation",

author = "Siobhan Crittenden and Marie Goepp and Jolinda Pollock and Calum Robb 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 J{\"u}rgen Schwarze 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 M} and Chengcan Yao",

year = "2021",

month = feb,

day = "12",

doi = "10.1126/sciadv.abd7954",

language = "English",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

}

Crittenden, S, Goepp, M, Pollock, J, Robb, C, 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, J, Breyer, RM, Arends, MJ, O'donnell, VB, Iredale, JP, Anderton, SM, Narumiya, S, Maizels, RM, Rossi, AG, Howie, SEM & Yao, C 2021, 'Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells', Science Advances. 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

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

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 M

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 crosstalk 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. Taken 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 crosstalk 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. Taken together, our findings provide emergent evidence that PGE2-mediated disruption of microbiota-Treg communication fosters intestinal inflammation

U2 - 10.1126/sciadv.abd7954

DO - 10.1126/sciadv.abd7954

M3 - Article

SN - 2375-2548

JO - Science Advances

JF - Science Advances

ER -

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

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Projects

Investigating the immune mechanisms underlying NSAID chemoprevention of colorectal cancer

To delineate immune mechanisms for limiting asthma development and severity

Equipment

Institute for Regeneration and Repair Flow Cytometry Facility

Cite this