Leddy, Robert S.Hudachek, Cinthia L.Phelan, Hannah M.Aherne, Carol M.Romero, JuliánHillard, Cecilia J.Wang, ZhiranEissner, GüntherJedlicka, PaulCollins, Colm B.2026-09-292026-09-292026-07Leddy, R S, Hudachek, C L, Phelan, H M, Aherne, C M, Romero, J, Hillard, C J, Wang, Z, Eissner, G, Jedlicka, P & Collins, C B 2026, 'CB 2 R promotes T cell gut homing and exacerbates ileitis in a murine Crohn’s model', Inflammatory Bowel Diseases, vol. 32, no. 7, pp. 1219-1234. https://doi.org/10.1093/ibd/izag0661078-0998PubMedCentral: PMC13337297https://hdl.handle.net/10641/8351Publisher Copyright: © The Author(s) 2026. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.El tráfico de leucocitos es un paso crítico en el desarrollo de enfermedades intestinales crónicas como la enfermedad de Crohn. Si bien las estrategias que bloquean el homing intestinal han obtenido éxitos parciales, esta enfermedad sigue sin cura, lo que deja una necesidad clínica insatisfecha. Este es el primer trabajo que describe un papel de la señalización del receptor de cannabinoides 2 (CB2R) en la promoción de la inducción mediada por ácido retinoico del heterodímero de integrinas α4β7 asociado al homing intestinal. Utilizando modelos in vitro e in vivo, caracterizamos los efectos de agonistas farmacológicos y agonistas inversos de CB2R sobre la expresión de receptores de homing de linfocitos T y la transmigración a través de barreras endoteliales asociadas al intestino. Este proceso dependiente de la quinasa regulada por señales extracelulares coincide con un aumento de la adherencia de linfocitos T en respuesta a la agonismo de CB2R con JWH-133. Estos efectos se revirtieron con el agonista inverso GP-1a de manera dependiente de CB2R. La eliminación selectiva de CB2R mediante CRISPR in vitro o en ratones CD4Cre/+ floxed in vivo dio lugar a una adherencia endotelial deteriorada y una disminución de la diapédesis hacia la lámina propia ileal. La eliminación específica de linfocitos T del gen CNR2, que codifica CB2R, atenuó la ileítis murina crónica caracterizada por una disminución de la infiltración de linfocitos T vírgenes y la pérdida de la arquitectura tisular en ratones TNFΔARE/+ de 20 semanas de edad. Este estudio apoya el desarrollo terapéutico adicional de fármacos dirigidos a CB2R para el tratamiento de la enfermedad inflamatoria intestinal. [Traducción automática al español; idioma original: inglés.]Leukocyte trafficking is a critical step in the development of chronic intestinal diseases such as Crohn’s disease. 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 α4β7. 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–dependent 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–specific deletion of CNR2, the gene encoding CB2R, attenuated chronic murine ileitis characterized by decreased naïve T cell infiltration and loss of tissue architecture in 20-week-old TNFΔARE/+ mice. This study supports further therapeutic development of CB2R-targeting drugs for the treatment of inflammatory bowel disease.172817382enghttp://creativecommons.org/licenses/by-nc-nd/4.0/CBRT cell adherencecannabinoidschronic ileitisImmunology and AllergyGastroenterologyYesjournal articleopen access10.1093/ibd/izag066https://www.scopus.com/pages/publications/105043866679https://www.scopus.com/pages/publications/105043866679#tab=citedBy