Macrophage HIF-2α suppresses NLRP3 inflammasome activation and alleviates insulin resistance

  • Cell Rep. 2021 Aug 24;36(8):109607. doi: 10.1016/j.celrep.2021.109607.
Xiaopeng Li  1 ,  Xiujuan Zhang  2 ,  Jialin Xia  1 ,  Linqi Zhang  1 ,  Bo Chen  1 ,  Guan Lian  1 ,  Chuyu Yun  1 ,  Juan Yang  1 ,  Yu Yan  1 ,  Pengcheng Wang  1 ,  Xuemei Wang  1 ,  Bo Liu  1 ,  Huiying Liu  1 ,  Hui Liang  3 ,  Yanli Pang  4 ,  Xian Wang  5 ,  Changtao Jiang  6
Affiliations
  • 1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
  • 2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Institute of Systems Biomedicine, School of Basic Medicine, Peking University, Beijing 100191, China.
  • 4. Department of Obstetrics and Gynecology, Third Hospital, Peking University, Beijing, China.
  • 5. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 6. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China. Electronic address: [email protected].
PMID: 34433035 DOI: 10.1016/j.celrep.2021.109607
Abstract

The interrelation between hypoxia and immune response has pivotal roles in the pathogenesis of chronic metabolic diseases. However, the role of macrophage HIF-2α in NLRP3 inflammasome activation remains unclear. Here, we show that deficiency of HIF-2α in macrophages results in excessive activation of the NLRP3 inflammasome in a manner dependent on CPT1A-mediated enhancement of fatty acid oxidation (FAO). Mechanistically, HIF-2α binds directly to the Cpt1a promoter and is involved in the regulation of H3K27me3 methylation during NLRP3 inflammasome activation. Myeloid-specific Hif2α knockout mice exhibit exacerbated Insulin resistance and increased activation of NLRP3 inflammasome in macrophages. Overexpression of the Hif2α gene or stabilization of the protein by FG-4592 ameliorates Insulin resistance and reduces NLRP3 inflammasome activation in macrophages. Taken together, our results suggest that macrophage HIF-2α inhibits FAO-mediated activation of the NLRP3 inflammasome and alleviates Insulin resistance.

Keywords
Cpt1a; EPAS1; FG-4592; H3K27me3; NLRP3 inflammasome; fatty acid oxidation; hypoxia inducible factor 2; insulin resistance; macrophage; methylation.
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