Cannabinoid CB2R regulates T cell gut-homing in preclinical Crohns model.

Abstract

Leukocyte trafficking is a critical step in development of chronic intestinal diseases such as Crohns 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 two (CB2R) signalling in promoting retinoic acid-mediated induction of the gut-homing associated integrin heterodimer 4{beta}7. Using in vitro and in vivo models, we characterised the effects of pharmacological CB2R agonists and inverse agonists on T cell homing receptor expression and transmigration across gut-associated endothelial barriers. This ERK-dependent process coincides with increased T cell adherence in response to CB2R agonism with JWH133. 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 characterised by decreased naive T cell infiltration and loss of tissue architecture in 20wk TNF{Delta}ARE/+mice. This study supports further therapeutic development of CB2R-blocking drugs for the treatment of inflammatory bowel disease.