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

TL;DR

The study shows that SerpinB2 helps tissue-resident macrophages survive by regulating mitochondrial function, which is crucial during chronic inflammation like obesity.

Contribution

The novel finding is that SerpinB2 regulates mitochondrial function and macrophage survival in chronic inflammation.

Findings

SerpinB2 promotes macrophage survival by regulating mitochondrial oxidative phosphorylation and preventing cytochrome c release.

Chronic inflammation reduces SerpinB2 expression, leading to a decline in VAT resident macrophages.

Restoring SerpinB2 or glutathione improves macrophage survival and metabolic health in mice.

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.

How cellular metabolism influences tissue-resident macrophage survival is currently unknown. The authors here demonstrate that SerpinB2 regulates mitochondrial function to promote tissue-resident macrophage survival.

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