Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Meyers, Allison K.; Wang, Zhan; Han, Wenzheng; Zhao, Qingxia; Zabalawi, Manal; Liu, Juan; Manne, Rajesh K; Lin, Hui-Kuan; Furdui, Cristina M.; Locasale, Jason W.; McCall, Charles E.; Zhu, Xuewei

Activating macrophage NLRP3 inflammasome can promote excessive inflammation, leading to severe cell and tissue damage and organ dysfunction. Here, we showed that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuated macrophage NLRP3 inflammasome activation. Broad rewiring of intracellular metabolism and enhanced autophagic flux occurred in inflammasome-activated macrophages, but neither was necessary for the PDHK-regulated reduction of NLRP3 inflammasome activity. PDHK inhibition protected against inflammation-induced mitochondrial fragmentation and cristae remodeling and improved mitochondrial function by repurposing mitochondria from ROS production to ATP generation. Inhibition of PDHK increased the expression of the mitochondrial fusion protein optic atrophy-1 (OPA1). Suppression of OPA1 partially reversed the effect of PDHK inhibition on NLRP3 inflammasome activation. In conclusion, our study suggests that inhibition of PDHK dampens macrophage NLRP3 inflammasome activation during acute inflammation by ameliorating mitochondrial damage in a mechanism separate from its canonical role as a metabolic regulator.