Caspase-11 regulates systemic inflammation and cell death in a cell-specific manner after trauma with shock.

Abstract

Severe trauma releases damage-associated molecular patterns (DAMPs), which activate the immune system via pattern recognition receptors. This triggers inflammatory cascades that can lead to systemic inflammatory response syndrome, immunosuppression, and multiple organ dysfunction syndrome. Pyroptosis is an inflammatory form of cell death mediated by caspase-11 and gasdermin D (GsdmD). In this study, we examined caspase-11's effects on inflammation, tissue damage, and neutrophil infiltration in a model of severe tissue injury. Male C57BL/6J (WT), caspase-11-/-, cell-specific caspase-11-/- mice (endothelial-specific caspase-11-/- [casp11EC-/-]), platelet-specific caspase-11-/- (casp11plt-/-), and hepatocyte-specific caspase-11-/- (casp11HC-/-) mice were subjected to polytrauma, consisting of hemorrhagic shock (25% total blood volume removed), liver crush, and bilateral lower extremity injury. At 6 h post-polytrauma, blood, plasma, and tissues were collected for analysis. Western blot analysis showed caspase-11 and GsdmD cleavage in the lungs and liver in WT mice at 6 h after polytrauma. GsdmD cleavage was found to be caspase-11 dependent. Inflammatory mediators, plasma IL-6 and CXCL-1/KC, were significantly increased in caspase-11-/-, casp11HC-/- and casp11EC-/- mice compared to WT controls or casp11plt-/-. Liver damage (ALT/AST) was similar between groups. Circulating neutrophil counts were decreased in caspase-11-/-, but neutrophils and neutrophil myeloperoxidase levels were increased in caspase-11-/- liver compared with WT after polytrauma. Our study identifies an unexpected and novel anti-inflammatory function for caspase-11 in trauma, through the regulation of neutrophil influx into tissues. Our findings underscore the significance of caspase-11 activation early after polytrauma to moderate trauma-induced inflammation.