title: Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation.
abstract: Caspase-8, an executioner enzyme in the death receptor pathway, was shown to initiate apoptosis and suppress necroptosis. In this study, we identify a novel, cell death-independent role for caspase-8 in dendritic cells (DCs): DC-specific expression of caspase-8 prevents the onset of systemic autoimmunity. Failure to express caspase-8 has no effect on the lifespan of DCs but instead leads to an enhanced intrinsic activation and, subsequently, more mature and autoreactive lymphocytes. Uncontrolled TLR activation in a RIPK1-dependent manner is responsible for the enhanced functionality of caspase-8-deficient DCs, because deletion of the TLR-signaling mediator, MyD88, ameliorates systemic autoimmunity induced by caspase-8 deficiency. Taken together, these data demonstrate that caspase-8 functions in a cell type-specific manner and acts uniquely in DCs to maintain tolerance.
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Carla M
authors.initials: CM
authors.lastname: Cuda
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Misharin
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Angelica K
authors.initials: AK
authors.lastname: Gierut
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Rana
authors.initials: R
authors.lastname: Saber
authors.affiliation: Department of Pathology, School of Medicine, Yale University, New Haven, CT 06510;
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Haines
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Jack
authors.initials: J
authors.lastname: Hutcheson
authors.affiliation: Division of Biological Sciences, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hedrick
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: G Scott
authors.initials: GS
authors.lastname: Budinger
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Christian
authors.initials: C
authors.lastname: Stehlik
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; h-perlman@northwestern.edu.
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8