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MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice

Affiliations
  • 1Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China.
  • 2Shenzhen Research Institute, The Hong Kong Polytechnic University, Hong Kong SAR, China.
  • 3Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai, China.
  • 4Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, China.
  • 5Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 6Prenatal Diagnostic Center and Cord Blood Bank, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 7Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Beijing, China.
  • 8The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China.
  • 9Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 10Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong SAR, China.
  • 11School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 12Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China. kenneth.ky.cheng@polyu.edu.hk.
  • 13Shenzhen Research Institute, The Hong Kong Polytechnic University, Hong Kong SAR, China. kenneth.ky.cheng@polyu.edu.hk.

Published on:

October 4, 2024

Abstract

M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways.