Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation

作者：Sathish Babu Vasamsetti, Samreen Sadaf, Mohammad A. Uddin, Jixing Shen, Ebin Johny, Awishi Mondal, Jonathan Florentin, Liqun Lei, Aleef Mannan, K. Murali Krishna Rao, John Sembrat, M. Montelongo Rojas, Ian Sipula, JAKE KASTROLL, Michael J. Jurczak, Sruti S. Shiva, Robert M. O’Doherty, Vijay Yechoor, Partha Dutta · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-69196-4 · 被引用次数：11 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Immune cells in cancer、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

How cellular metabolism facilitates tissue-resident macrophage maintenance remains elusive. Here we show that visceral adipose tissue (VAT)-resident macrophages, unlike monocyte-derived macrophages, are enriched with mitochondrial-specific antioxidant enzymes restraining inflammation and promoting VAT homeostasis and insulin sensitivity. Additionally, VAT resident macrophages express high levels of plasminogen activator inhibitor type 2, encoded by SerpinB2, which is involved in the blood coagulation cascade. SerpinB2 promotes adipose resident macrophage survival by regulating mitochondrial oxidative phosphorylation and preventing the release of pro-apoptotic cytochrome c from the mitochondria into the cytoplasm via antioxidant glutathione production. Chronic inflammation, such as obesity, diminishes SerpinB2 expression in VAT macrophages in patients and mice, leading to the decline of this macrophage subset. Mechanistically, interferon-γ elevation in diabetes induces Ikaros, a transcriptional suppressor, which binds to the SerpinB2 promoter and decreases SerpinB2 expression. Congruently, selective depletion of the IFN-γ receptor in myeloid cells or supplementation of macrophage-specific SerpinB2 deficient mice with N-acetylcysteine, a glutathione precursor, restores VAT resident macrophage survival, decreases adipocyte size, and improves glucose tolerance and insulin sensitivity. Our data thus reveal an unexpected function of SerpinB2 in the regulation of mitochondrial funct...