Eosinophil-derived COX-2 protects against experimental colitis through the PGE <sub>2</sub> –IL-22 axis
Abstract
Inflammatory bowel disease (IBD) is driven by a breakdown in immune regulation and epithelial barrier function, yet the contribution of eosinophils to this process has remained poorly defined and controversial. While eosinophils infiltrate the intestinal mucosa during both flares and remission, their role in shaping disease outcomes is unclear. Our RNA-seq analyses of colonic eosinophils isolated from dextran sulfate sodium (DSS)-treated mice revealed a significant upregulation of cyclooxygenase (COX)-2 (gene name, Ptgs2 ). Eosinophil-specific deletion of COX-2 (Ptgs2 fl/fl eoCre +/− ) reduced IL-22 production and exacerbated DSS- and trinitrobenzene sulfonic acid (TNBS)-induced colitis, characterized by greater weight loss, higher disease activity, colon shortening, and epithelial injury. Administration of recombinant IL-22 reversed these phenotypes. Mechanistically, eosinophil-derived COX-2 enhanced IL-22 production by type 3 Innate lymphoid cells (ILC3s) through prostaglandin E2 (PGE 2 ) signaling. Consistently, Ptgs2 fl/fl eoCre +/− mice exhibited reduced colonic PGE 2 levels, while PGE 2 analog treatment restored IL-22 production and mucosal protection. Our findings identify eosinophil-derived COX-2 and PGE 2 as a critical regulator of IL-22 production during colitis, uncovering a eosinophil–ILC3 cross talk that safeguards the intestinal barrier and represents a promising therapeutic target in IBD.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Yang Yang
Constance L. Atkins
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston
Yuanyuan Fan
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston
Lidan Hou
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston
Jie Zhao
Junda Gao
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston
Yankai Wen
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston
Nicolas F. Moreno
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston
Xiangsheng Huang
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston
Faraz Bishehsari
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston
Agnieszka K. Czopik
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston
Sean P. Colgan
Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Tugrul Purnak
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston
Keith C. Summa
Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University
Yingzi Cong
Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University
Elizabeth A. Jacobsen
Division of Allergy, Asthma and Clinical Immunology, Mayo Clinic
Cynthia Ju
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston