CB2R promotes T cell gut homing and exacerbates ileitis in a murine Crohn's model

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.