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RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation
A new Cell paper published by the Oberst Lab reveals breakthrough findings indicating an unexpected diversity in the outcomes of RIPK1 and RIPK3 signaling within the central nervous system not observed in other tissues. Congratulations to Brian P. Daniels, Annelise G. Snyder, Tayla M. Olsen, Susana Orozco, Thomas H. Oguin III, Stephen W.G. Tait, Jennifer Martinez, Michael Gale Jr., Yueh-Ming Loo, and Andrew Oberst.
- Mice lacking RIPK3 are highly susceptible to neuroinvasive West Nile virus
- RIPK3 signaling in WNV-infected neurons results in inflammatory chemokine expression
- WNV-infected, RIPK3-deficient mice display a fatal defect in chemokine-dependent neuroinflammation
- Direct activation of RIPK3 in neurons triggers chemokine production but not cell death
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.