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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,\n                  <jats:italic>Ptgs2<\/jats:italic>\n                  ). Eosinophil-specific deletion of Cox-2 (Ptgs2\n                  <jats:sup>fl\/fl<\/jats:sup>\n                  eoCre\n                  <jats:sup>+\/-<\/jats:sup>\n                  ) 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\n                  <jats:sub>2<\/jats:sub>\n                  ) signaling. Consistently, Ptgs2\n                  <jats:sup>fl\/fl<\/jats:sup>\n                  eoCre\n                  <jats:sup>+\/-<\/jats:sup>\n                  mice exhibited reduced colonic PGE\n                  <jats:sub>2<\/jats:sub>\n                  levels, while PGE\n                  <jats:sub>2<\/jats:sub>\n                  analog treatment restored IL-22 production and mucosal protection. Our findings identify eosinophil-derived COX-2 and PGE\n                  <jats:sub>2<\/jats:sub>\n                  as a critical regulator of IL-22 production during colitis, uncovering a previously unrecognized eosinophil-ILC3 crosstalk that safeguards the intestinal barrier and represents a promising therapeutic target in IBD.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    The role of eosinophils in inflammatory bowel disease (IBD) has remained unresolved. We identify eosinophil-derived COX-2 as the main source of prostaglandin E2 (PGE\n                    <jats:sub>2<\/jats:sub>\n                    ) in colitis, which drives IL-22 production by ILC3s to maintain epithelial protection. This discovery defines a protective eosinophil\/PGE\n                    <jats:sub>2<\/jats:sub>\n                    \/IL-22 circuit and reveals a therapeutic target to strengthen barrier defense in IBD.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.18.695257","type":"posted-content","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T20:00:17Z","timestamp":1766433617000},"source":"Crossref","is-referenced-by-count":1,"title":["Eosinophil-derived COX-2 protects against experimental colitis through the PGE\n                  <sub>2<\/sub>\n                  -IL-22 axis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0942-1800","authenticated-orcid":false,"given":"Yang","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance L.","family":"Atkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidan","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junda","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yankai","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas F.","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangsheng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faraz","family":"Bishehsari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Czopik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean P.","family":"Colgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tugrul","family":"Purnak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith C.","family":"Summa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzi","family":"Cong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Jacobsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Ju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025122412000937000_2025.12.18.695257v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(16)31711-1"},{"key":"2025122412000937000_2025.12.18.695257v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)32126-2"},{"key":"2025122412000937000_2025.12.18.695257v1.3","doi-asserted-by":"crossref","unstructured":"A. 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