Sabrina Sofia Burgener

Abstract Signal shutdown mechanisms must exist to silence the potent inflammatory programs initiated by the caspase-1 (CASP1) protease, to allow inflammation to resolve and reinstate tissue homeostasis. It is unknown how CASP1 terminates its activity in vivo. Here, we use a knock-in mouse model in which the CASP1 CARD domain linker (CDL) is mutated to prevent self-cleavage (Casp1.CDL mice) to show that CASP1 CDL autoproteolysis terminates CASP1 activity in vivo.

Abstract In Gram-negative bacterial sepsis, excessive caspase 4/11 activation in response to circulating bacterial lipid LPS (endotoxemia) can cause organ damage and mortality. Current inhibitors of caspase 4/11 also block caspase 1 activity and are therefore not appealing clinical candidates for treating Gram-negative sepsis.

Highlights • Serpinb1a and Serpinb6a prevent cathepsin G-dependent neutrophil death • Cathepsin G cleaves gasdermin D at Leu274 to generate a p30 fragment • Serpin deficiency leads to high inflammation via cathepsin G and gasdermin D • Gasdermin D does not regulate neutrophil death in serpin deficiency Summary Neutrophil granule serine proteases contribute to immune responses through cleavage of microbial toxins and structural proteins.