Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death

PLoS Pathogens

Andrew Oberst¹  Jennifer T. Grier²  Meghan A. Wynosky-Dolfi²  Alexandra DeLaney²  Igor E. Brodsky²  Lance W. Peterson³  Jorge Henao-Mejia³  Naomi H. Philip³  Anthony Rongvaux³  Erin E. Zwack³  Melanie Santos-Marrero³  Baofeng Hu³  Yan Sun³  Tayla M. Olsen³  Scott D. Pope³  Carolina B. López⁴  Daniel P. Beiting⁵ 

[1] Fred Hutchinson Cancer Research Center, Clinical Research Division and Program in Immunology, Seattle, Washington, United States of America;University of Pennsylvania Perelman School of Medicine, Institute for Immunology, Philadelphia, Pennsylvania, United States of America;University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America;University of Washington, Department of Immunology, Seattle, Washington, United States of America;Yale University School of Medicine, Department of Immunobiology, New Haven, Connecticut, United States of America

关键词: Gene expression;    Cytokines;    Inflammation;    Apoptosis;    Yersinia;    Macrophages;    Gene regulation;    Necrosis;   

DOI  :  10.1371/journal.ppat.1005910

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Caspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infection by multiple pathogens including Yersinia, but whether this is due to death of infected cells or an intrinsic role of caspase-8 in TLR-induced gene expression is unknown. Caspase-8 activation at death signaling complexes results in its autoprocessing and subsequent cleavage and activation of its downstream apoptotic targets. Whether caspase-8 activity is also important for inflammatory gene expression during bacterial infection has not been investigated. Here, we report that caspase-8 plays an essential cell-intrinsic role in innate inflammatory cytokine production in vivo during Yersinia infection. Unexpectedly, we found that caspase-8 enzymatic activity regulates gene expression in response to bacterial infection as well as TLR signaling independently of apoptosis. Using newly-generated mice in which caspase-8 autoprocessing is ablated (Casp8DA/DA), we now demonstrate that caspase-8 enzymatic activity, but not autoprocessing, mediates induction of inflammatory cytokines by bacterial infection and a wide variety of TLR stimuli. Because unprocessed caspase-8 functions in an enzymatic complex with its homolog cFLIP, our findings implicate the caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new insight into regulation of antibacterial immune defense.

【 授权许可】

CC BY