Journal Article

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

Beiting, Daniel P., López, Carolina B., Henao-Mejia, Jorge, DeLaney, Alexandra, Philip, Naomi H., Oberst, Andrew, Santos-Marrero, Melanie, Grier, Jennifer T., Sun, Yan, Olsen, Tayla M., Wynosky-Dolfi, Meghan A., Rongvaux, Anthony, Pope, Scott D., Zwack, Erin E., Hu, Baofeng, Peterson, Lance W., Brodsky, Igor E.

2016

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animals / Apoptosis / Bacterial diseases / Bacterial infections / Biology and Life Sciences / Caspase 8 - immunology / Caspase 8 - metabolism / Caspases / Cell death / Cytokines / Cytokines - biosynthesis / Disease Models, Animal / Dogs / Environmental stress / Enzymatic activity / Enzyme-Linked Immunosorbent Assay / Flow Cytometry / Gene expression / Gene Expression Regulation - immunology / Gene Knockdown Techniques / Health aspects / Immune system / Immunity, Innate - immunology / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Mortality / Polymerase Chain Reaction / Risk factors / Signal Transduction - immunology / Toll-like receptors / Toll-Like Receptors - immunology / Veterinary colleges / Yersinia / Yersinia Infections - immunology