Monoacylglycerol Lipase Regulates Secretion of Endocannabinoids from Human Monocyte-Derived Dendritic Cells

Abstract

Monoacylglycerol lipase (MGLL) is a serine hydrolase required for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2AG) to downstream eicosanoids. 2AG has been shown to modulate immune cell function but its role in human primary innate immune cells remains unclear. Moreover, it is not known whether 2AG may function to signal between human immune cells as a corollary to its known function in the central nervous system. Here, we profiled serine hydrolases in human monocyte-derived dendritic cells (moDC) using activity-based protein profiling and discovered MGLL to be induced upon ligation of multiple pattern recognition receptors (PRRs). Using the selective small molecule inhibitor JZL184 we demonstrated that MGLL regulates cellular 2AG and related endocannabinoids. The absence of MGLL activity did not affect maturation or the production of pro-inflammatory cytokines in these cells. Critically, MGLL regulated the abundance of secreted 2AG highlighting potential paracrine roles on bystander cells.