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

Dan Weng; Robyn Marty-Roix; Sandhya GanesanMegan K. ProulxGregory I. VladimerWilliam J. KaiserEdward S. MocarskiKimberly PouliotFrancis Ka-Ming ChanMichelle A. KelliherPhillip A. HarrisJohn BertinPeter J. GoughDmitry M. ShayakhmetovJon D. GoguenKatherine A. FitzgeraldNeal SilvermanEgil Lien

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

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

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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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第20期|7391-7396|共6页
作者
Dan Weng; Robyn Marty-Roix; Sandhya GanesanMegan K. ProulxGregory I. VladimerWilliam J. KaiserEdward S. MocarskiKimberly PouliotFrancis Ka-Ming ChanMichelle A. KelliherPhillip A. HarrisJohn BertinPeter J. GoughDmitry M. ShayakhmetovJon D. GoguenKatherine A. FitzgeraldNeal SilvermanEgil Lien;
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作者单位

Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605;

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605;

Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University, Atlanta, GA 30322;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
killing; absence; transcription;

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

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