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

TitleProstaglandin E₂ constrains systemic inflammation through an innate lymphoid cell-IL-22 axis.
Publication TypeJournal Article
Year of Publication2016
AuthorsDuffin 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
JournalScience
Volume351
Issue6279
Pagination1333-8
Date Published2016 Mar 18
ISSN1095-9203
KeywordsAnimals, Bacterial Infections, Dinoprostone, Gene Expression, Humans, Immunity, Innate, Inflammation, Interleukins, Intestines, Lymphocytes, Mice, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction
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.

DOI10.1126/science.aad9903
Alternate JournalScience
PubMed ID26989254
PubMed Central IDPMC4841390
Grant ListG0901697 / / Medical Research Council / United Kingdom
106122 / / Wellcome Trust / United Kingdom
/ / Medical Research Council / United Kingdom
I01 BX000616 / BX / BLRD VA / United States
BB/K091121/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
MR/K013386/1 / / Medical Research Council / United Kingdom
G1000868 / / Medical Research Council / United Kingdom
R01 DK037097 / DK / NIDDK NIH HHS / United States
DK37097 / DK / NIDDK NIH HHS / United States
MR/L012766/1 / / Medical Research Council / United Kingdom
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