Cutting Edge: FAS (CD95) Mediates Noncanonical IL-1b and IL-18 Maturation via Caspase-8 in an RIP3-Independent Manner

Fas, a TNF family receptor, is activated by the membrane protein Fas ligand expressed on various immune cells. Fas signaling triggers apoptosis and induces inflammatory cytokine production. Among the Fasinduced cytokines, the IL-1b family cytokines require proteolysis to gain biological activity. Inflammasomes, which respond to pathogens and danger signals, cleave IL-1b cytokines via caspase-1. However, the mechanisms by which Fas regulates IL-1b activation remain unresolved. In this article, we demonstrate that macrophages exposed to TLR ligands upregulate Fas, which renders them responsive to receptor engagement by Fas ligand. Fas signaling activates caspase-8 in macrophages and dendritic cells, leading to the maturation of IL-1b and IL-18 independently of inflammasomes or RIP3. Hence, Fas controls a novel noncanonical IL1b activation pathway in myeloid cells, which could play an essential role in inflammatory processes, tumor surveillance, and control of infectious diseases. The Journal of Immunology, 2012, 189: 000–000.