Mitochondrial uncoupling protein 1 antagonizes atherosclerosis by blocking NLRP3 inflammasome-dependent interleukin-1 production

Mitochondrial uncoupling protein 1 (UCP1) is the hallmark of brown adipocytes responsible for cold- and diet-induced thermogenesis. Here, we report a previously unidentified role of UCP1 in maintaining vascular health through its anti-inflammatory actions possibly in perivascular adipose tissue. UCP1 deficiency exacerbates dietary obesity-induced endothelial dysfunction, vascular inflammation, and atherogenesis in mice, which was not rectified by reconstitution of UCP1 in interscapular brown adipose tissue. Mechanistically, lack of UCP1 augments mitochondrial membrane potential and mitochondrial superoxide, leading to hyperactivation of the NLRP3-inflammasome and caspase-1-mediated maturation of interleukin-1 beta (IL-1 beta). UCP1 deficiency-evoked deterioration of vascular dysfunction and atherogenesis is reversed by IL-1 beta neutralization or a chemical mitochondrial uncoupler. Furthermore, UCP1 knockin pigs (which lack endogenous UCP1) are refractory to vascular inflammation and coronary atherosclerosis. Thus, UCP1 acts as a gatekeeper to prevent NLRP3 inflammasome activation and IL-1 beta production in the vasculature, thereby conferring a protective effect against cardiovascular diseases.