AI Article Synopsis

  • M1 macrophages help protect against infections but can also contribute to diseases related to metabolism and inflammation, driven by the E3 ubiquitin ligase MDM2.
  • MDM2 enhances the production of inflammatory molecules like IL-1β, MCP-1, and nitric oxide (NO) in M1 macrophages by degrading SPSB2, which stabilizes iNOS and activates the HIF-1α pathway.
  • Deleting MDM2 in immune cells reduces inflammation and damage in obesity and sepsis models, but may lead to higher mortality and bacterial infections when M1 macrophage responses are suppressed.

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452520PMC
http://dx.doi.org/10.1038/s41467-024-53006-wDOI Listing

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