Vanilloid receptor 1 acts as a regulator of immune homeostasis in the gut (MUC8P.731)

Abstract

Abstract Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipids. Endogenous intestinal cannabinoids such as Anandamide, control appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we show that Anandamide and its vanilloid receptor, VR1, mediate immune homeostasis in the gut and pancreas. Capsaicin, a vanilloid, with which Anandamide shares VR1, acts similarly. 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. Treatment of mice with capsaicin 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. Our study unveils a novel role for cannabinoids in maintaining immune homeostasis in the gut/pancreas, and reveals a new conversation between the nervous and immune systems, using distinct receptors.