Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Zhan Wang
Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Wenzheng Han
Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
Qingxia Zhao
Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Manal Zabalawi
Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Likun Duan
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA
Juan Liu
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA
Qianyi Zhang
Department of Biology, Wake Forest University, Winston-Salem, NC 27109, USA
Rajesh K. Manne
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Felipe Lorenzo
Section on Endocrinology and Metabolism, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Matthew A. Quinn
Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Qianqian Song
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Daping Fan
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA
Hui-Kuan Lin
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Cristina M. Furdui
Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Jason W. Locasale
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA
Charles E. McCall
Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Xuewei Zhu
Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Corresponding author
Summary: 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 suggestsa non-canonical role of mitochondrial PDHK in promoting mitochondrial stress and supporting NLRP3 inflammasome activation during acute inflammation.
