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

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

  • Nat Commun. 2024 Oct 4;15(1):8624. doi: 10.1038/s41467-024-53006-w.
Kelvin Ka-Lok Wu 1 2,  Xiaofan Xu 1,  Manyin Wu 1,  Xiaomu Li 3,  Moinul Hoque 1,  Gloria Hoi Yee Li 1,  Qizhou Lian 4 5 6,  Kekao Long 1,  Tongxi Zhou 1,  Hailong Piao 7,  Aimin Xu 8 9 10,  Hannah Xiaoyan Hui 11,  Kenneth King-Yip Cheng 12 13
Affiliations

Affiliations

  • 1 Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China.
  • 2 Shenzhen Research Institute, The Hong Kong Polytechnic University, Hong Kong SAR, China.
  • 3 Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai, China.
  • 4 Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, China.
  • 5 Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 6 Prenatal Diagnostic Center and Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 7 Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Beijing, China.
  • 8 The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China.
  • 9 Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 10 Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong SAR, China.
  • 11 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 12 Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China. kenneth.ky.cheng@polyu.edu.hk.
  • 13 Shenzhen Research Institute, The Hong Kong Polytechnic University, Hong Kong SAR, China. kenneth.ky.cheng@polyu.edu.hk.
PMID: 39366973 DOI: 10.1038/s41467-024-53006-w
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.

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