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.
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Rodger
authors.initials: R
authors.lastname: Duffin
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: O'Connor
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Crittenden
authors.affiliation: Division of Pathway Medicine, Edinburgh Infectious Diseases, The University of Edinburgh, Edinburgh EH16 4SB, UK.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Forster
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Cunjing
authors.initials: C
authors.lastname: Yu
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Institute for Immunology and Infection Research, The University of Edinburgh, Edinburgh EH9 3JT, UK.
authors.forename: Danielle
authors.initials: D
authors.lastname: Smyth
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Calum T
authors.initials: CT
authors.lastname: Robb
authors.affiliation: MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Christos
authors.initials: C
authors.lastname: Skouras
authors.affiliation: Department of Gastroenterology, First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
authors.forename: Shaohui
authors.initials: S
authors.lastname: Tang
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: James
authors.initials: J
authors.lastname: Richards
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: Pellicoro
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Weller
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37212, USA. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Mole
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics (AK Project), Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 102-0075, Japan.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.affiliation: Institute for Immunology and Infection Research, The University of Edinburgh, Edinburgh EH9 3JT, UK.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
authors.affiliation: Division of Pathway Medicine, Edinburgh Infectious Diseases, The University of Edinburgh, Edinburgh EH16 4SB, UK. Centre for Synthetic and Systems Biology (SynthSys), The University of Edinburgh, Edinburgh EH9 3JD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Ghazal
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Howie
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.affiliation: Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK. chengcan.yao@ed.ac.uk.
authors.forename: Chengcan
authors.initials: C
authors.lastname: Yao
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D007378:Interleukins / Q000276:immunology*; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D000097043:Interleukin-22
chemical_list: D015232:Dinoprostone; D007378:Interleukins; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000097043:Interleukin-22