title: Cutting edge: FAS (CD95) mediates noncanonical IL-1β and IL-18 maturation via caspase-8 in an RIP3-independent manner.
abstract: 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 Fas-induced cytokines, the IL-1β family cytokines require proteolysis to gain biological activity. Inflammasomes, which respond to pathogens and danger signals, cleave IL-1β cytokines via caspase-1. However, the mechanisms by which Fas regulates IL-1β 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-1β and IL-18 independently of inflammasomes or RIP3. Hence, Fas controls a novel noncanonical IL-1β activation pathway in myeloid cells, which could play an essential role in inflammatory processes, tumor surveillance, and control of infectious diseases.
authors.affiliation: Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bossaller
authors.forename: Ping-I
authors.initials: PI
authors.lastname: Chiang
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidt-Lauber
authors.forename: Sandhya
authors.initials: S
authors.lastname: Ganesan
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.forename: Vijay A K
authors.initials: VA
authors.lastname: Rathinam
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
authors.forename: Deepa
authors.initials: D
authors.lastname: Subramanian
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Neal
authors.initials: N
authors.lastname: Silverman
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D053200:Fas-Associated Death Domain Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D058847:Inflammasomes / Q000378:metabolism / Q000502:physiology; D020382:Interleukin-18 / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000502:physiology*
chemical_list: C505534:Fadd protein, mouse; C491899:Fas protein, mouse; D053200:Fas-Associated Death Domain Protein; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D019014:fas Receptor; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8