PROJECT SUMMARY Sepsis is a formidable public health problem, and there is a need to better understand the basic mechanisms of sepsis and immunomodulation. Our studies will define the anti-inflammatory mechanisms and functional effects in sepsis of N-oleoyl dopamine (OLDA) and N-arachidonoyl dopamine (NADA), which are endogenous acyl-dopamines produced in the peripheral and central nervous systems (PNS, CNS). OLDA and NADA exhibit activity at the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1R). In mice with S. aureus pneumonia, intraabdominal polymicrobial sepsis, or endotoxemia, we found that OLDA or NADA administration 1) induces an early substantial upregulation of systemic IL-10, 2) decreases pro-inflammatory cytokines and chemokines, and 3) reduces acute lung injury and sepsis scores at 24 hours. NADA also reduces CGRP and increases Substance P in the plasmas of LPS-treated mice. Our studies in bone marrow chimeras of Trpv1-/- and wild-type mice indicated that NADA induces IL-10 via TRPV1 expressed by non- myeloid cells. Our further preliminary data suggest that neuronal TRPV1 mediates the anti-inflammatory and protective actions of OLDA in LPS-treated mice, and more specifically, that these effects are mediated by TRPV1 neurons in the CNS rather than the PNS. Finally, we observed increased plasma and brain levels of OLDA and NADA in LPS-treated mice, which suggest that these novel endogenous lipids may be dynamically regulated during acute inflammation and sepsis. Collectively, our data have led to our central hypothesis that there is a CNS based neuro-immunomodulatory link that involves the activation of neuronal TRPV1 by endogenous lipids, such as OLDA and NADA, and regulates inflammatory responses and outcomes of acute inflammation and sepsis. Aim #1 will localize the TRPV1 neurons responsible for the anti-inflammatory actions of OLDA and NADA in acute inflammation and sepsis and determine the role of CB1R in the TRPV1-dependent anti-inflammatory actions of OLDA and NADA. Aim #2 will identify the downstream mechanisms by which the activation of neuronal TRPV1 by OLDA or NADA upregulates IL-10 production by circulating monocytes in sepsis, focusing on the roles of Substance P, CGRP, and the sympathetic nervous system. Aim #3 will define the effects of OLDA and NADA on sepsis outcomes, and the effects of sepsis on endogenous production of OLDA and NADA, and expression of TRPV1 and CB1R. These studies will advance the understanding of the neuro-immunomodulatory effects and endogenous roles of NADA, OLDA and TRPV1 in sepsis, with the ultimate goal to identify novel therapeutic targets.