Journal article
Caspase-8 promotes c-Rel-dependent inflammatory cytokine expression and resistance against Toxoplasma gondii
Proceedings of the National Academy of Sciences - PNAS, v 116(24), pp 11926-11935
11 Jun 2019
PMID: 31147458
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Caspase-8 is a key integrator of cell survival and cell death decisions during infection and inflammation. Following engagement of tumor necrosis factor superfamily receptors or certain Toll-like receptors (TLRs), caspase-8 initiates cell-extrinsic apoptosis while inhibiting RIPK3-dependent programmed necrosis. In addition, caspase-8 has an important, albeit less well understood, role in cell-intrinsic inflammatory gene expression. Macrophages lacking caspase-8 or the adaptor FADD have defective inflammatory cytokine expression and inflammasome priming in response to bacterial infection or TLR stimulation. How caspase-8 regulates cytokine gene expression, and whether caspase-8-mediated gene regulation has a physiological role during infection, remain poorly defined. Here we demonstrate that both caspase-8 enzymatic activity and scaffolding functions contribute to inflammatory cytokine gene expression. Caspase-8 enzymatic activity was necessary for maximal expression of
and
, but caspase-8 deficient cells exhibited a further decrease in expression of these genes. Furthermore, the ability of TLR stimuli to induce optimal IκB kinase phosphorylation and nuclear translocation of the nuclear factor kappa light chain enhancer of activated B cells family member c-Rel required caspase activity. Interestingly, overexpression of c-Rel was sufficient to restore expression of IL-12 and IL-1β in caspase-8-deficient cells. Moreover,
mice were unable to control infection by the intracellular parasite
, which corresponded to defects in monocyte recruitment to the peritoneal cavity, and exogenous IL-12 restored monocyte recruitment and protection of caspase-8-deficient mice during acute toxoplasmosis. These findings provide insight into how caspase-8 controls inflammatory gene expression and identify a critical role for caspase-8 in host defense against eukaryotic pathogens.
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Details
- Title
- Caspase-8 promotes c-Rel-dependent inflammatory cytokine expression and resistance against Toxoplasma gondii
- Creators
- Alexandra A DeLaney - University of PennsylvaniaCorbett T Berry - Drexel UniversityDavid A Christian - University of PennsylvaniaAndrew Hart - University of PennsylvaniaElisabet Bjanes - University of PennsylvaniaMeghan A Wynosky-Dolfi - University of PennsylvaniaXinyuan Li - University of PennsylvaniaBart Tummers - St. Jude Children's Research HospitalIrina A Udalova - Arthritis Research UKYouhai H Chen - University of PennsylvaniaUri Hershberg - Drexel UniversityBruce D Freedman - University of PennsylvaniaChristopher A Hunter - University of PennsylvaniaIgor E Brodsky - University of Pennsylvania
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 116(24), pp 11926-11935
- Publisher
- PNAS
- Grant note
- R21 AI125924 / NIAID NIH HHS MR/J001899/1 / Medical Research Council R21 AI126042 / NIAID NIH HHS R01 AI128530 / NIAID NIH HHS R01 AI139102 / NIAID NIH HHS R01 AI041158 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000471039700058
- Scopus ID
- 2-s2.0-85067203284
- Other Identifier
- 991019167328104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Immunology