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

Kelvin Ka-lok Wu, Xiaofan Xu, Manyin Wu, Xiaomu Li, Moinul Hoque, Gloria Hoi Yee Li, Qizhou Lian, Kekao Long, Tongxi Zhou, Hailong Piao, Aimin Xu, Hannah Xiaoyan Hui and Kenneth King-yip Cheng ()
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Kelvin Ka-lok Wu: The Hong Kong Polytechnic University
Xiaofan Xu: The Hong Kong Polytechnic University
Manyin Wu: The Hong Kong Polytechnic University
Xiaomu Li: Zhongshan Hospital Fudan University
Moinul Hoque: The Hong Kong Polytechnic University
Gloria Hoi Yee Li: The Hong Kong Polytechnic University
Qizhou Lian: Shenzhen Institute of Advanced Technology
Kekao Long: The Hong Kong Polytechnic University
Tongxi Zhou: The Hong Kong Polytechnic University
Hailong Piao: Chinese Academy of Sciences
Aimin Xu: The University of Hong Kong
Hannah Xiaoyan Hui: The Chinese University of Hong Kong
Kenneth King-yip Cheng: The Hong Kong Polytechnic University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53006-w

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