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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Systemic inflammation, resulting from massive release of pro-inflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are incompletely 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 treating with EP4 agonists. Mechanistically, we demonstrate that PGE2–EP4 signaling directly acts 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, PGE2–EP4 signaling inhibits systemic inflammation through ILC/IL-22 axis–dependent protection of gut barrier dysfunction.
Original languageEnglish
Pages (from-to)1333-1338
Number of pages6
JournalScience
Volume351
Issue number6279
DOIs
Publication statusPublished - 18 Mar 2016

Keywords

  • NONSTEROIDAL ANTIINFLAMMATORY DRUGS
  • SEVERE SEPSIS
  • SEPTIC SHOCK
  • BARRIER
  • CELLS
  • INTERLEUKIN-22
  • PANCREATITIS
  • MULTICENTER
  • MORTALITY
  • INFECTION

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