Lipid talk: Endocannabinoids regulate mucosal inflammation following helminth infection

Abstract

Abstract More than 2 billion humans carry infectious parasites leading to chronic co-morbidities and growth retardation in children. Parasitic infections induce a T helper type 2 (Th2) immune response in the host to promote clearance which can lead to fibrosis if chronic. We recently showed that infection with the soil-transmitted nematode Nippostrongylus brasiliensis (Nb) induces overproduction of endocannabinoids (eCBs) in the host. Endocannabinoids are endogenous cannabis-like molecules that influence the development of obesity and are anti-inflammatory, however their function in infection is largely unknown. The overproduction of eCBs in Nb-infected mice was observed throughout infection in the infected lung and intestine. Pharmacological inhibition of cannabinoid receptor subtype 1 (CB-1R) with AM6545 (10 mg/Kg/2mL), a peripherally-restricted CB1R neutral antagonist, throughout Nb infection exacerbated weight loss of mice without altering food or water intake. This inhibition of CB1Rs led to a prolonged presence of eosinophils and neutrophils in the broncho-alveolar fluid and an accumulation of lymphocytes in the spleen. Furthermore, CB1R inhibition caused an increase in the expression of the mannose receptor on alveolar macrophages at day 8 post infection, indicating a sustained need for inflammatory resolution. Strikingly, we also found that Nb produces its own eCBs which vary in concentration based on stage of development, and that the eCB system is present in many parasitic nematodes including those that infect humans. These findings suggest that the eCB system is active in several hookworm species, and that host and helminth eCBs may influence immune and anti-inflammatory functions.