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

• Published in: Science (American Association for the Advancement of Science) Vol. 351; no. 6279; pp. 1333 - 1338
• Main Authors: Duffin, Rodger, O'Connor, Richard A., Crittenden, Siobhan, Forster, Thorsten, Yu, Cunjing, Zheng, Xiaozhong, Smyth, Danielle, Robb, Calum T., Rossi, Fiona, Skouras, Christos, Tang, Shaohui, Richards, James, Pellicoro, Antonella, Weller, Richard B., Breyer, Richard M., Mole, Damian J., Iredale, John P., Anderton, Stephen M., Narumiya, Shuh, Maizels, Rick M., Ghazal, Peter, Howie, Sarah E., Rossi, Adriano G., Yao, Chengcan
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 18.03.2016; The American Association for the Advancement of Science
• Subjects: Anatomy; Animals; Bacterial diseases; Bacterial infections; Bacterial Infections - genetics; Bacterial Infections - immunology; Cells; Dinoprostone - immunology; Gene Expression; Humans; Immune system; Immunity, Innate; Inflammation - drug therapy; Inflammation - immunology; Inflammation - microbiology; Inflammatory diseases; Interleukin-22; Interleukins - immunology; Intestines - immunology; Intestines - microbiology; Lymphatic system; Lymphocytes - immunology; Mice; Receptors, Prostaglandin E, EP4 Subtype - antagonists & inhibitors; Receptors, Prostaglandin E, EP4 Subtype - genetics; Receptors, Prostaglandin E, EP4 Subtype - immunology; Risk factors; Signal Transduction; Translocation
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aad9903

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.