DNTP catabolism is a macrophage-intrinsic gatekeeper preventing NLRP3 inflammasome hyperactivation

Abstract

Abstract Aberrant activation of NLRP3 inflammasome drives the development of many diseases, including atherosclerosis, gout, osteoarthritis, Alzheimer’s disease, macular degeneration, type 2 diabetes and cancer. Our recent work demonstrated that new mitochondrial DNA (mtDNA) synthesis, initiated at the inflammasome priming step, is a prerequisite for producing oxidized mtDNA (ox-mtDNA)—an activating ligand of NLRP3. However, little is known regarding how innate immune cells, such as macrophages, manage to prevent NLRP3 inflammasome hyperactivation under physiological conditions, thereby avoiding the development of immunopathology. Here we show that SAMHD1, a cytosolic dNTP hydrolase, functions as a macrophage-intrinsic gatekeeper that restricts NLRP3 inflammasome hyperactivation. Mechanistically, inflammasome priming activates SAMHD1 to inhibit cytosolic dNTP buildup, thereby preventing their transport into mitochondria. This in turn protects mitochondria from uncontrolled new mtDNA synthesis and ox-mtDNA production, ultimately attenuating the extent of NLRP3 inflammasome activation. Consistent with these findings, SAMHD1-deficient mice exhibited NLRP3 inflammasome hyperactivation and developed exacerbated immunopathology in vivo relative to their wild-type littermates in response to various inflammatory insults. Together, these results establish cytosolic dNTP catabolism as a physiologically important protective mechanism to restrict NLRP3 hyperactivation, thereby linking dysregulation of nucleotide metabolism with the onset of NLRP3-dependent immunopathology. Supported by NIH (K22AI135074, R35GM142654), CPRIT (#RR180014)