Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death

• Type of Material: Article
• Authors: Dan Weng, University of Massachusetts; Robyn Marty-Roix, University of Massachusetts; Sandhya Ganesan, University of Massachusetts; Megan K. Proulx, University of Massachusetts; Gregory I. Vladimer, University of Massachusetts; William Kaiser, Emory University; Edward Mocarski, Emory University; Kimberly Pouliot, University of Massachusetts; Francis Ka-Ming Chan, University of Massachusetts; Michelle A. Kelliher, University of Massachusetts; Phillip A. Harris, GlaxoSmithKline; John Bertin, GlaxoSmithKline; Peter J. Gough, GlaxoSmithKline; Dmitry Shayakhmetov, Emory University; Jon D. Goguen, University of Massachusetts; Katherine A. Fitzgerald, University of Massachusetts; Neal Silverman, University of Massachusetts; Egil Lien, University of Massachusetts
• Language: English
• Date: 2014-05-20
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2014 PNAS
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1403477111
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 111
• Issue: 20
• Start Page: 7391
• End Page: 7396
• Grant/Funding Information: The work was supported by National Institutes of Health (NIH) Grants AI07538 and AI057588-American Recovery and Reinvestment Act (to E.L.), AI060025 (to N.S.), AI64349 and AI083713 (to K.A.F.), and AI095213 (to G.I.V. and N.S.), the Norwegian Cancer Society, and the Research Council of Norway.; The study also used core services supported by University of Massachusetts Diabetes and Endocrinology Research Center Grant DK32520 and the University of Massachusetts Core Electron Microscopy Facility (supported by NIH/National Center for Research Resources Award S10RR027897).
• Keywords: ACTIVATION; IL-1-BETA; MACROPHAGES; EFFECTOR YOPJ; YERSINIA-PESTIS; Science & Technology; III SECRETION SYSTEM; DENDRITIC CELLS; INFLAMMASOME; MULTIDISCIPLINARY SCIENCES; Science & Technology - Other Topics; INFECTION; NF-KAPPA-B; Multidisciplinary Sciences

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.