Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Activating the macrophage NLRP3 inflammasome can promote excessive inflammation with severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages and septic mice by lowering caspase-1 cleavage and interleukin-1β (IL-1β) secretion. Inhibiting PDHK reverses NLRP3 inflammasome-induced metabolic reprogramming, enhances autophagy, promotes mitochondrial fusion over fission, preserves crista ultrastructure, and attenuates mitochondrial reactive oxygen species (ROS) production. The suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of its canonical role as a pyruvate dehydrogenase regulator. Our study suggests a non-canonical role of mitochondrial PDHK in promoting mitochondrial stress and supporting NLRP3 inflammasome activation during acute inflammation. [Display omitted] •PDHK supports NLRP3 inflammasome activation•PDHK promotes mitochondrial fragmentation in acutely inflamed macrophages•PDHK impairs autophagic flux and mitophagy in acutely inflamed macrophages•PDHK inhibition attenuates NLRP3 inflammasome activation in vitro and in vivo Meyers et al. uncover a non-canonical role of mitochondrial pyruvate dehydrogenase kinase (PDHK) in promoting mitochondrial stress and activating the NLRP3 inflammasome during acute inflammation. Pharmacological inhibition or genetic ablation of PDHK significantly improves mitochondrial fitness and attenuates NLRP3 inflammasome activation in murine or human macrophages and septic mice.