Immune regulation by the endocannabinoid N-arachidonoyl dopamine (NADA)

Arachidonic acid-based lipids, or eicosanoids, are well-known regulators of the inflammatory response. While there are additional classes of eicosanoids that have also been shown to possess immunomodulatory activity, such as the cannabinoids, they remain largely unstudied. We have found that the endocannabinoid N-arachidonoyl dopamine (NADA) decreases inflammatory responses in vitro in endothelial cells after challenge with TLR agonists, and that this activity is dependent upon the cannabinoid receptors (CB1R and CB2R). Furthermore, NADA dramatically reduces systemic inflammation in murine models of bacterial lipopeptide, endotoxemia, and polymicrobial intraabdominal sepsis. Consistent with its classification as a potent endovanilloid, the activity of NADA in vivo depends upon the cation channel transient receptor potential vanilloid 1 (TRPV1) expressed in non-hematopoietic cells and may be mediated through neuronal TRPV1. Furthermore, the activity of NADA systemically, in endothelial cells, and in the hematopoietic compartment is dependent upon CB2R. Finally, we show that the immunomodulatory activity of NADA is mediated in part by its ability to regulate prostanoid production, and its metabolism into the novel lipid prostaglandin D2- dopamine. These data indicate that NADA can modulate inflammatory activation as both an endocannabinoid and endovanilloid, and suggests that these pathways may be targeted therapeutically for the treatment of acute inflammatory disorders, such as sepsis