Cathepsin G Inhibition by Serpinb1 and Serpinb6 Prevents Programmed Necrosis in Neutrophils and Monocytes and Reduces GSDMD-Driven Inflammation.

ABSTRACT: Neutrophil granule serine proteases contribute to immune responses through cleavage of microbial toxins and structural proteins. They induce tissue damage and modulate inflammation if levels exceed their inhibitors. Here, we show that the intracellular protease inhibitors Serpinb1a and Serpinb6a contribute to monocyte and neutrophil survival in steady-state and inflammatory settings by inhibiting cathepsin G (CatG). Importantly, we found that CatG efficiently cleaved gasdermin D (GSDMD) to generate the signature N-terminal domain GSDMD-p30 known to induce pyroptosis. Yet GSDMD deletion did not rescue neutrophil survival in Sb1a.Sb6a^-/- mice. Furthermore, Sb1a.Sb6a^-/- mice released high levels of pro-inflammatory cytokines upon endotoxin challenge in vivo in a CatG-dep

SUBMITTER: Burgener SS 

PROVIDER: S-EPMC7350907 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature