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While strategies that block gut homing have yielded partial success, this disease remains uncurable leaving an unmet clinical need. This is the first paper to describe a role for cannabinoid receptor 2 (CB2R) signaling in promoting retinoic acid-mediated induction of the gut homing associated integrin heterodimer \u03b14\u03b27. Using in vitro and in vivo models, we characterized the effects of pharmacological CB2R agonists and inverse agonists on T cell homing receptor expression and transmigration across gut-associated endothelial barriers. This extracellular signal-regulated kinase\u2013dependent process coincides with increased T cell adherence in response to CB2R agonism with JWH-133. These effects were reversed with an inverse agonist GP-1a in a CB2R dependent manner. Selective deletion of CB2R using CRISPR in vitro or CD4Cre\/+ floxed mice in vivo resulted in impaired endothelial cell adherence and decreased diapedesis into the ileal lamina propria. T cell\u2013specific deletion of CNR2, the gene encoding CB2R, attenuated chronic murine ileitis characterized by decreased na\u00efve\u00a0T cell infiltration and loss of tissue architecture in 20-week-old TNF\u0394ARE\/+ mice. This study supports further therapeutic development of CB2R-targeting drugs for the treatment of inflammatory bowel disease.<\/jats:p>","DOI":"10.1093\/ibd\/izag066","type":"journal-article","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T12:47:31Z","timestamp":1774702051000},"page":"1219-1234","source":"Crossref","is-referenced-by-count":5,"title":["CB2R promotes T cell gut homing and exacerbates ileitis in a murine Crohn\u2019s model"],"prefix":"10.1093","volume":"32","author":[{"given":"Robert S","family":"Leddy","sequence":"first","affiliation":[{"name":"School of Biomolecular and Biomedical Science, University College Dublin , Dublin,","place":["Ireland"]},{"name":"UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin , Dublin,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinthia L","family":"Hudachek","sequence":"additional","affiliation":[{"name":"Section of Gastroenterology, Hepatology and 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