Cathepsin G inhibition by Serpinb1 and Serpinb6 prevents programmed necrosis in neutrophils and monocytes and reduces GSDMD-driven inflammation

Sabrina Sofia Burgener, Nathan Georges François Leborgne, Scott J. Snipas, Guy S. Salvesen, Phillip Ian Bird, Charaf Benarafa

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

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-dependent manner. Canonical inflammasome activation in Sb1a.Sb6a−/− macrophages showed increased IL-1β release that was dependent on CatG and GSDMD. Together, our findings demonstrate that cytosolic serpins expressed in myeloid cells prevent cell death and regulate inflammatory responses by inhibiting CatG and alternative activation of GSDMD.

Original languageEnglish
Pages (from-to)3646-3656
Number of pages11
JournalCell Reports
Volume27
Issue number12
DOIs
Publication statusPublished - 18 Jun 2019

Keywords

  • apoptosis
  • cathepsin
  • cell death
  • elastase
  • gasdermin
  • inflammation
  • neutrophil
  • proteinase
  • pyroptosis
  • serpin

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