2. Academic Validation
  3. Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation

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

  • Nat Commun. 2026 Feb 12;17(1):1493. doi: 10.1038/s41467-026-69196-4.
Sathish Babu Vasamsetti # 1 2,  Samreen Sadaf # 1,  Mohammad A Uddin 1,  Jixing Shen 1,  Ebin Johny 1,  Awishi Mondal 1,  Jonathan Florentin 1,  Liqun Lei 1,  Aleef Mannan 1,  Krithika Sudhakar Rao 1,  John Sembrat 1,  Mauricio Rojas 3,  Ian Sipula 4,  Jake Kastroll 4,  Michael J Jurczak 4 5,  Sruti Shiva 1 6,  Robert M O'Doherty 1 4,  Vijay Yechoor 1 4,  Partha Dutta 7 8 9 10 11 12
Affiliations

Affiliations

  • 1 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
  • 2 Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 3 Division of Pulmonary, Critical Care, & Sleep Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA.
  • 4 Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 6 Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 7 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 8 Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 9 Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 10 Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 11 The Center for Cardiovascular Inflammation, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 12 Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA. [email protected].
  • # Contributed equally.
PMID: 41680163 DOI: 10.1038/s41467-026-69196-4
Abstract

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 function and survival of tissue-resident macrophages.

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