title: Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death.
abstract: 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.
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.|University of Pennsylvania Perelman School of Medicine, Institute for Immunology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Naomi H
authors.identifier: http://orcid.org/0000-0002-1475-8635
authors.initials: NH
authors.lastname: Philip
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Alexandra
authors.initials: A
authors.lastname: DeLaney
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.|University of Pennsylvania Perelman School of Medicine, Institute for Immunology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Lance W
authors.identifier: http://orcid.org/0000-0003-2458-6678
authors.initials: LW
authors.lastname: Peterson
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.|University of Pennsylvania Perelman School of Medicine, Institute for Immunology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: Santos-Marrero
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Grier
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Meghan A
authors.identifier: http://orcid.org/0000-0002-2985-3918
authors.initials: MA
authors.lastname: Wynosky-Dolfi
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Zwack
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Baofeng
authors.initials: B
authors.lastname: Hu
authors.affiliation: University of Washington, Department of Immunology, Seattle, Washington, United States of America.
authors.forename: Tayla M
authors.initials: TM
authors.lastname: Olsen
authors.affiliation: Fred Hutchinson Cancer Research Center, Clinical Research Division and Program in Immunology, Seattle, Washington, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rongvaux
authors.affiliation: Yale University School of Medicine, Department of Immunobiology, New Haven, Connecticut, United States of America.
authors.forename: Scott D
authors.identifier: http://orcid.org/0000-0002-5243-3639
authors.initials: SD
authors.lastname: Pope
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.|University of Pennsylvania Perelman School of Medicine, Institute for Immunology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Carolina B
authors.initials: CB
authors.lastname: López
authors.affiliation: University of Washington, Department of Immunology, Seattle, Washington, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Oberst
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.|University of Pennsylvania Perelman School of Medicine, Institute for Immunology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Beiting
authors.affiliation: University of Pennsylvania Perelman School of Medicine, Institute for Immunology, Philadelphia, Pennsylvania, United States of America.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jorge
authors.identifier: http://orcid.org/0000-0001-8894-2227
authors.initials: J
authors.lastname: Henao-Mejia
authors.affiliation: University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America.|University of Pennsylvania Perelman School of Medicine, Institute for Immunology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Igor E
authors.initials: IE
authors.lastname: Brodsky
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D055785:Gene Knockdown Techniques; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology; D015009:Yersinia Infections / Q000276:immunology*
chemical_list: D016207:Cytokines; D051193:Toll-Like Receptors; C505526:Casp8 protein, mouse; D053181:Caspase 8