See Abstract page RELEVANCE (See instructions): We will continue to study the role of mitochondrial DNA metabolism in NLRP3 inflammasome activation and the effect of NRF2 on macrophage polarization. We will examine whether the pathogenesis of osteoarthritis (OA) and Alzheimer’s disease (AD) in mice is accompanied by oxidized mitochondrial DNA generation, its cleavage and export to the cytosol. We will also test the ability of CMPK2 and Fen1 inhibitors to attenuate NLRP3 inflammasome activation in OA, AD and other disease models.