title: Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death.
abstract: A number of pathogens cause host cell death upon infection, and Yersinia pestis, infamous for its role in large pandemics such as the "Black Death" in medieval Europe, induces considerable cytotoxicity. The rapid killing of macrophages induced by Y. pestis, dependent upon type III secretion system effector Yersinia outer protein J (YopJ), is minimally affected by the absence of caspase-1, caspase-11, Fas ligand, and TNF. Caspase-8 is known to mediate apoptotic death in response to infection with several viruses and to regulate programmed necrosis (necroptosis), but its role in bacterially induced cell death is poorly understood. Here we provide genetic evidence for a receptor-interacting protein (RIP) kinase-caspase-8-dependent macrophage apoptotic death pathway after infection with Y. pestis, influenced by Toll-like receptor 4-TIR-domain-containing adapter-inducing interferon-β (TLR4-TRIF). Interestingly, macrophages lacking either RIP1, or caspase-8 and RIP3, also had reduced infection-induced production of IL-1β, IL-18, TNF, and IL-6; impaired activation of the transcription factor NF-κB; and greatly compromised caspase-1 processing. Cleavage of the proform of caspase-1 is associated with triggering inflammasome activity, which leads to the maturation of IL-1β and IL-18, cytokines important to host responses against Y. pestis and many other infectious agents. Our results identify a RIP1-caspase-8/RIP3-dependent caspase-1 activation pathway after Y. pestis challenge. Mice defective in caspase-8 and RIP3 were also highly susceptible to infection and displayed reduced proinflammatory cytokines and myeloid cell death. We propose that caspase-8 and the RIP kinases are key regulators of macrophage cell death, NF-κB and inflammasome activation, and host resistance after Y. pestis infection.
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine.
authors.forename: Dan
authors.initials: D
authors.lastname: Weng
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine.
authors.forename: Robyn
authors.initials: R
authors.lastname: Marty-Roix
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Microbiology and Physiological Systems.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Proulx
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Vladimer
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Pouliot
authors.affiliation: Department of Cancer Biology, and.
authors.forename: Francis Ka-Ming
authors.initials: FK
authors.lastname: Chan
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Kelliher
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426;
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Harris
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426;
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gough
authors.affiliation: Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University, Atlanta, GA 30322; and.
authors.forename: Dmitry M
authors.initials: DM
authors.lastname: Shayakhmetov
authors.affiliation: Department of Microbiology and Physiological Systems.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Goguen
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine,Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine.
authors.forename: Neal
authors.initials: N
authors.lastname: Silverman
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine,Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway Egil.Lien@umassmed.edu.
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
mesh_terms: D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology; D053181:Caspase 8 / Q000378:metabolism*; D016923:Cell Death; D016207:Cytokines / Q000378:metabolism; D007113:Immunity, Innate; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015009:Yersinia Infections / Q000382:microbiology; D015010:Yersinia pestis / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D016328:NF-kappa B; C109227:YopP protein, Yersinia; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8