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Title: Activity of uncleaved caspase-8 controls anti-bacterial immune defense and TLR-induced cytokine production independent of cell death      
keywords:
Transcriptome or Gene expression
ID:
PRJNA343025
description:
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. Overall design: Two biological replicates were analyzed for each of 6 conditions (three genotypes; two treatments per genotype)
accesstypes:
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA343025
authentication:
none
authorization:
none
ID:
pmid:27737018
name:
Mus musculus
ncbiID:
ncbitax:10090
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • R01 AI108685/AI/NIAID NIH HHS/United States

  • R01 AI103062/AI/NIAID NIH HHS/United States

  • R01 AI083284/AI/NIAID NIH HHS/United States

  • R21 AI117365/AI/NIAID NIH HHS/United States

  • R21 AI109267/AI/NIAID NIH HHS/United States

  • K12 GM081259/GM/NIGMS NIH HHS/United States

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