Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death.
Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death.
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DOI：
10.1371/journal.ppat.1005910
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发表时间：
2016-10
期刊：
影响因子：
6.7
通讯作者：
Brodsky IE
中科院分区：
文献类型：
--
作者：
Philip NH;DeLaney A;Peterson LW;Santos-Marrero M;Grier JT;Sun Y;Wynosky-Dolfi MA;Zwack EE;Hu B;Olsen TM;Rongvaux A;Pope SD;López CB;Oberst A;Beiting DP;Henao-Mejia J;Brodsky IE
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 (Casp8 DA/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. TLR signaling induces expression of key inflammatory cytokines and pro-survival factors that facilitate control of microbial infection. TLR signaling can also engage cell death pathways through activation of enzymes known as caspases. Caspase-8 activates apoptosis in response to infection by pathogens that interfere with NF-κB signaling, including Yersinia, but has also recently been linked to control of inflammatory gene expression. Pathogenic Yersinia can cause severe disease ranging from gastroenteritis to plague. While caspase-8 mediates cell death in response to Yersinia infection as well as other signals, its precise role in gene expression and host defense during in vivo infection is unknown. Here, we show that caspase-8 activity promotes cell-intrinsic cytokine expression, independent of its role in cell death in response to Yersinia infection. Our studies further demonstrate that caspase-8 enzymatic activity plays a previously undescribed role in ensuring optimal TLR-induced gene expression by innate cells during bacterial infection. This work sheds new light on mechanisms that regulate essential innate anti-bacterial immune defense.
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影响因子：
11.4
作者：
Aliprantis, AO;Yang, RB;Zychlinsky, A
通讯作者：
Zychlinsky, A
影响因子：
8
作者：
Besnault-Mascard, L;Leprince, C;Vazquez, A
通讯作者：
Vazquez, A
影响因子：
8.8
作者：
Dillon CP;Oberst A;Weinlich R;Janke LJ;Kang TB;Ben-Moshe T;Mak TW;Wallach D;Green DR
通讯作者：
Green DR
影响因子：
4.4
作者：
Beisner, DR;Ch'en, IL;Hedrick, SM
通讯作者：
Hedrick, SM
DOI：
10.1073/pnas.0806585105
发表时间：
2008-08-26
影响因子：
11.1
作者：
Chen, Nien-Jung;Chio, Iok In Christine;Mak, Tak W.
通讯作者：
Mak, Tak W.