Macrophage Inflammasome Activation Drives Anti-inflammatory Responses via Neutrophil-Derived ASC Speck Transfer and Gasdermin-Dependent Caspase-1 Inhibition

Abstract

Inflammasomes are critical components of the innate immune system, traditionally associated with pro-inflammatory responses. While the inflammasome in macrophages has been extensively studied and linked to pyroptosis and cytokine release, the neutrophil inflammasome remains poorly understood. Neutrophil inflammasome activation drives unique outcomes such as NETosis and robust IL-1{beta} production without inducing pyroptosis. In contrast, macrophage inflammasome activation promotes pyroptosis and the release of cytokines like IL-1 and IL-18. Here, using zebrafish models of Salmonella enterica serovar Typhimurium infection and COVID-19-associated cytokine storm syndrome (CSS), we reveal opposing roles of neutrophil and macrophage inflammasomes: neutrophil inflammasomes are pro-inflammatory, whereas macrophage inflammasomes mediate anti-inflammatory responses. We show that Gasdermin E- and Ninjurin-1-mediated cell death in neutrophils releases ASC specks, which are taken up by macrophages. This transfer negatively regulates caspase-1 activity via the C-terminal domain of Gasdermin E, promoting the resolution of inflammation. To our knowledge, this is the first study to reveal the anti-inflammatory role of the macrophage inflammasome, document the in vivo transfer of ASC specks between neutrophils and macrophages, and uncover the negative feedback regulation of the inflammasome by the C-terminal domain of Gsdme. These results offer novel insights into potential therapeutic approaches for hyperinflammatory diseases like bacterial infections and COVID-19-associated CSS.