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

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…

• NN
  National Natural Science Foundation of China

  Awards: 81970675, 92357305, 81970675, 92357305
• RG
  Research Grants Council, University Grants Committee

  Award: AoE/M/707-18
• HK
  Hong Kong Polytechnic University

  Awards: P0040979, P0036848