Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis

Rodger Duffin; Richard A. O'Connor; Siobhan Crittenden; Thorsten Forster; Cunjing Yu; Xiaozhong Zheng; Danielle Smyth; Calum T. Robb; Fiona Rossi; Christos Skouras; Shaohui Tang; James Richards; Antonella Pellicoro; Richard B. Weller; Richard M. Breyer; Damian J. Mole; John P. Iredale; Stephen M. Anderton; Shuh Narumiya; Rick M. Maizels; Peter Ghazal; Sarah E. Howie; Adriano G. Rossi; Chengcan Yao

doi:10.1126/science.aad9903

Prostaglandin E₂ constrains systemic inflammation through an innate lymphoid cell-IL-22 axis

Rodger Duffin, Richard A. O'Connor, Siobhan Crittenden, Thorsten Forster, Cunjing Yu, Xiaozhong Zheng, Danielle Smyth, Calum T. Robb, Fiona Rossi, Christos Skouras, Shaohui Tang, James Richards, Antonella Pellicoro, Richard B. Weller, Richard M. Breyer, Damian J. Mole, John P. Iredale, Stephen M. Anderton, Shuh Narumiya, Rick M. MaizelsPeter Ghazal, Sarah E. Howie, Adriano G. Rossi, Chengcan Yao

Cell Signalling and Immunology

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

144 Citations (Scopus)

Abstract

Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E₂ (PGE₂), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE₂ synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE₂-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC-IL-22 axis impairs PGE₂-mediated inhibition of systemic inflammation. Hence, the ILC-IL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE₂-EP4 signaling to impede systemic inflammation.

Original language	English
Pages (from-to)	1333-1338
Number of pages	6
Journal	Science
Volume	351
Issue number	6279
DOIs	https://doi.org/10.1126/science.aad9903
Publication status	Published - 18 Mar 2016

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/science.aad9903

Cite this

Duffin, R., O'Connor, R. A., Crittenden, S., Forster, T., Yu, C., Zheng, X., Smyth, D., Robb, C. T., Rossi, F., Skouras, C., Tang, S., Richards, J., Pellicoro, A., Weller, R. B., Breyer, R. M., Mole, D. J., Iredale, J. P., Anderton, S. M., Narumiya, S., ... Yao, C. (2016). Prostaglandin E₂ constrains systemic inflammation through an innate lymphoid cell-IL-22 axis. Science, 351(6279), 1333-1338. https://doi.org/10.1126/science.aad9903

@article{492940cba5134f4d83a4ebaf3fcc85bc,

title = "Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis",

abstract = "Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC-IL-22 axis impairs PGE2-mediated inhibition of systemic inflammation. Hence, the ILC-IL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation.",

author = "Rodger Duffin and O'Connor, {Richard A.} and Siobhan Crittenden and Thorsten Forster and Cunjing Yu and Xiaozhong Zheng and Danielle Smyth and Robb, {Calum T.} and Fiona Rossi and Christos Skouras and Shaohui Tang and James Richards and Antonella Pellicoro and Weller, {Richard B.} and Breyer, {Richard M.} and Mole, {Damian J.} and Iredale, {John P.} and Anderton, {Stephen M.} and Shuh Narumiya and Maizels, {Rick M.} and Peter Ghazal and Howie, {Sarah E.} and Rossi, {Adriano G.} and Chengcan Yao",

year = "2016",

month = mar,

day = "18",

doi = "10.1126/science.aad9903",

language = "English",

volume = "351",

pages = "1333--1338",

journal = "Science",

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Duffin, R, O'Connor, RA, Crittenden, S, Forster, T, Yu, C, Zheng, X, Smyth, D, Robb, CT, Rossi, F, Skouras, C, Tang, S, Richards, J, Pellicoro, A, Weller, RB, Breyer, RM, Mole, DJ, Iredale, JP, Anderton, SM, Narumiya, S, Maizels, RM, Ghazal, P, Howie, SE, Rossi, AG & Yao, C 2016, 'Prostaglandin E₂ constrains systemic inflammation through an innate lymphoid cell-IL-22 axis', Science, vol. 351, no. 6279, pp. 1333-1338. https://doi.org/10.1126/science.aad9903

TY - JOUR

T1 - Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis

AU - Duffin, Rodger

AU - O'Connor, Richard A.

AU - Crittenden, Siobhan

AU - Forster, Thorsten

AU - Yu, Cunjing

AU - Zheng, Xiaozhong

AU - Smyth, Danielle

AU - Robb, Calum T.

AU - Rossi, Fiona

AU - Skouras, Christos

AU - Tang, Shaohui

AU - Richards, James

AU - Pellicoro, Antonella

AU - Weller, Richard B.

AU - Breyer, Richard M.

AU - Mole, Damian J.

AU - Iredale, John P.

AU - Anderton, Stephen M.

AU - Narumiya, Shuh

AU - Maizels, Rick M.

AU - Ghazal, Peter

AU - Howie, Sarah E.

AU - Rossi, Adriano G.

AU - Yao, Chengcan

PY - 2016/3/18

Y1 - 2016/3/18

N2 - Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC-IL-22 axis impairs PGE2-mediated inhibition of systemic inflammation. Hence, the ILC-IL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation.

AB - Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC-IL-22 axis impairs PGE2-mediated inhibition of systemic inflammation. Hence, the ILC-IL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation.

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