2. Academic Validation
  3. Macrophage HIF-2α suppresses NLRP3 inflammasome activation and alleviates insulin resistance

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

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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