The Endocannabinoid System Acts As A Regulator Of Immune Homeostasis In The Gut

Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipids. Endogenous intestinal cannabinoids such as Anandamide (AEA), control appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a novel role for AEA and its vanilloid receptor (VR1) in the regulation of immune tolerance in the gut and the pancreas. This is the first demonstration of a major immunological role for an endocannabinoid. Capsaicin (CP), a vanilloid, with which AEA shares VR1, acts similarly. Specifically, we show that the engagement of the cannabinoid/vanilloid receptor augments the number and immune suppressive function of the regulatory CX3CR1hi macrophages, which express the highest levels of such receptors among the gut immune cells. Additionally, mice that are genetically deficient in VR1 have reduced proportions of CX3CR1hi macrophages in the gut under normal homeostatic conditions. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4+ T cells called Tr1 cells in an IL27 dependent manner both in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of VR1 can be transferred to naïve NOD mice (model of type 1 diabetes) by transfer of CD4+ T cells. Further, oral administration of AEA to NOD mice provides protection from type 1 diabetes. Our study unveils a novel role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas, and reveals a new conversation between the nervous and immune systems, using distinct receptors