RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation.
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.
['Daniels|Brian P|BP|', 'Snyder|Annelise G|AG|', 'Olsen|Tayla M|TM|', 'Orozco|Susana|S|', 'Oguin|Thomas H|TH|', 'Tait|Stephen W G|SWG|', 'Martinez|Jennifer|J|', 'Gale|Michael|M|', 'Loo|Yueh-Ming|YM|', 'Oberst|Andrew|A|']
D000818:Animals D002490:Central Nervous System D018925:Chemokines D007962:Leukocytes D008264:Macrophages D051379:Mice D008810:Mice, Inbred C57BL D009336:Necrosis D009474:Neurons D053422:Receptor-Interacting Protein Serine-Threonine Kinases D014901:West Nile Fever D014902:West Nile virus
RIPK3 neuroinflammation necroptosis West Nile virus chemokines RIPK1 neuroimmunology