CANNABINOID 2 RECEPTOR AND GPR55 AS THERAPEUTIC TARGETS IN EXPERIMENTAL SEPSIS

Abstract

Sepsis represents a dysregulated systemic acute inflammatory response to severe infection. Despite efforts to develop supportive sepsis therapies, none has been approved that address the immune dysregulation. The endogenous cannabinoid system becomes active during sepsis and may present a novel axis for controlling inflammation. In the present study, our aim was to determine the impact of cannabinoid 2 receptor and G protein-coupled receptor 55 (GPR55) modulation on the inflammatory response, using a murine sepsis model. Using intravital microscopy, leukocyte activity was evaluated within the intestinal microvasculature. We observed that sepsis-induced increased leukocyte adhesion was diminished by inhibition of endocannabinoid degradation by JZL184 or GPR55 antagonists. Leukocyte rolling was diminished during sepsis, and this was significantly reversed by inhibition of endocannabinoid degradation. However, we failed to observe a direct effect of cannabinoids on neutrophil migration in vitro. Modulation of the endocannabinoid response had consequences on the cytokines secreted into the blood during sepsis; in particular, GPR55 agonists heightened TNF and IL-1β levels. Thus, our data suggest an important role of endocannabinoid system including GPR55 in the host response in experimental sepsis, hinting there may be a novel therapeutic candidate within the endocannabinoid system for the treatment of sepsis-induced dysregulation of the inflammatory response.