S-14 : Inflammasomes have extracellular activities that propagate inflammation

Abstract

Microbes or endogenous danger signals trigger the assembly of cytosolic inflammasome receptors with the adapter ASC into speck-like aggregates. ASC specks recruit and activate caspase-1, which induces IL-1β cytokine maturation and pyroptotic cell death. We found that after inflammasome activation and pyroptotic cell death of activated macrophages fully assembled inflammasomes accumulated in the extracellular environment. Extracellular inflammasomes retained biological activity as they mediated further pro-caspase-1 and pro-IL-1β processing in the extracellular space. In addition, macrophages were found to phagocytose extracellular inflammasomes leading to lysosomal damage, activation of the NLRP3 inflammasome as well as nucleation of soluble ASC in the cytosol of cells that had phagocytosed inflammasomes. These processes resulted in caspase-1 activation and further propagation of IL-1β responses. Extracellular inflammasomes were also found in bodily fluids of patients with inflammatory diseases and in mouse models after experimental inflammasome activation. Moreover, anti-ASC Abs were identified in sera of patients and animals with autoimmunity. Anti-ASC Abs opsonized extracellular inflammasomes leading to further amplification of inflammatory responses in vitro and in vivo. Together, these findings reveal extracellular functions of inflammasomes that can act to perpetuate inflammatory responses.