title: RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation.
abstract: Receptor-interacting protein kinase-3 (RIPK3) is an activator of necroptotic cell death, but recent work has implicated additional roles for RIPK3 in inflammatory signaling independent of cell death. However, while necroptosis has been shown to contribute to antiviral immunity, death-independent roles for RIPK3 in host defense have not been demonstrated. Using a mouse model of West Nile virus (WNV) encephalitis, we show that RIPK3 restricts WNV pathogenesis independently of cell death. Ripk3-/-mice exhibited enhanced mortality compared to wild-type (WT) controls, while mice lacking the necroptotic effector MLKL, or both MLKL and caspase-8, were unaffected. The enhanced susceptibility of Ripk3-/-mice arose from suppressed neuronal chemokine expression and decreased central nervous system (CNS) recruitment of T lymphocytes and inflammatory myeloid cells, while peripheral immunity remained intact. These data identify pleiotropic functions for RIPK3 in the restriction of viral pathogenesis and implicate RIPK3 as a key coordinator of immune responses within the CNS.
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Daniels
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Annelise G
authors.initials: AG
authors.lastname: Snyder
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Tayla M
authors.initials: TM
authors.lastname: Olsen
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Orozco
authors.affiliation: Immunity, Inflammation, and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Oguin
authors.affiliation: Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
authors.forename: Stephen W G
authors.initials: SWG
authors.lastname: Tait
authors.affiliation: Immunity, Inflammation, and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109, USA; Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109, USA; Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109, USA. Electronic address: looy@uw.edu.
authors.forename: Yueh-Ming
authors.initials: YM
authors.lastname: Loo
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109, USA; Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109, USA. Electronic address: oberst@uw.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Oberst
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D018925:Chemokines / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009474:Neurons / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D014901:West Nile Fever / Q000276:immunology*; D014902:West Nile virus / Q000502:physiology*
chemical_list: D018925:Chemokines; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse
keywords: RIPK1; RIPK3; West Nile virus; chemokines; necroptosis; neuroimmunology; neuroinflammation