Abstract 1579 Endocannabinoid biosynthetic enzymes signal through LKB1-AMPK in macrophage inflammation and pain response

Diacylglycerol lipase-beta (DAGLB) functions as a principal 2-arachidonoylglycerol (2-AG) biosynthetic enzyme most well known for its role in endocannabinoid and eicosanoid metabolism in immune cells including macrophages and dendritic cells. Genetic or pharmacological disruption of DAGLB ameliorates inflammation and hyper-nociception in behavioral models of pain. These beneficial effects have been ascribed principally to reductions in downstream pro-inflammatory lipid signaling; whether alternative mechanisms of regulation could explain these effects have been largely under explored. Here, we describe the application of quantitative chemical- and phospho-proteomics to discover that disruption of DAGLB in primary macrophages leads to LKB1-AMPK signaling activation, resulting in reprogramming of the phosphoproteome and bioenergetics. Importantly, AMPK inhibition reversed the antinociceptive effects of DAGLB disruption and supports DAGLB-AMPK crosstalk in vivo. Our findings uncover signaling between endocannabinoid biosynthetic pathways and ancient energy sensing kinases to mediate cell biological and pain responses. Support by the National Institutes of Health (Grants DA053107, P30DA033934, P01HL120840, DA043571, GM144472 and 5P30CA044579), National Science Foundation (CHE-1942467), the Robbins Family MRA Young Investigator Award from the Melanoma Research Alliance, the Owens FamilyFoundation, and the MarkFoundation for Cancer Research Emerging Leader Award.