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Cell. 2017 Apr 6;169(2):301-313.e11. doi: 10.1016/j.cell.2017.03.011. Epub 2017 Mar 30.

RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation.

Author information

1
Department of Immunology, University of Washington, Seattle, WA 98109, USA.
2
Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA.
3
Immunity, Inflammation, and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709, USA.
4
Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
5
Department of Immunology, University of Washington, Seattle, WA 98109, USA; Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109, USA.
6
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.
7
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.

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.

KEYWORDS:

RIPK1; RIPK3; West Nile virus; chemokines; necroptosis; neuroimmunology; neuroinflammation

Comment in

PMID:
28366204
PMCID:
PMC5405738
DOI:
10.1016/j.cell.2017.03.011
[Indexed for MEDLINE]
Free PMC Article

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