TY - JOUR
T1 - IL-1 reprogramming of adult neural stem cells limits neurocognitive recovery after viral encephalitis by maintaining a proinflammatory state
AU - Soung, Allison L.
AU - Davé, Veronica A.
AU - Garber, Charise
AU - Tycksen, Eric D.
AU - Vollmer, Lauren L.
AU - Klein, Robyn S.
N1 - Funding Information:
The authors would like to thank W. Beatty at the Molecular Microbiology Imaging facility at Washington University School of Medicine, the Washington University Center for Cellular Imaging (WUCCI), and A. Yoo for critical reading of the manuscript. This work was support by NSF grant DGE-1745038 to A.L.S. and NIH grants R01NS116788, R01NS104471, and R012052632 to R.S.K. A.L.S. and R.S.K. designed the experiments. A.L.S. V.A.D. C.G. and L.L.V. performed experiments. A.L.S. V.A.D. R.S.K. and E.D.T. analyzed the data. A.L.S. and R.S.K. wrote the paper. All authors read and edited the manuscript.
Funding Information:
The authors would like to thank W. Beatty at the Molecular Microbiology Imaging facility at Washington University School of Medicine, the Washington University Center for Cellular Imaging (WUCCI), and A. Yoo for critical reading of the manuscript. This work was support by NSF grant DGE-1745038 to A.L.S. and NIH grants R01NS116788, R01NS104471, and R012052632 to R.S.K.
Publisher Copyright:
© 2021 The Author(s)
PY - 2022/1
Y1 - 2022/1
N2 - Innate immune responses to emerging RNA viruses are increasingly recognized as having significant contributions to neurologic sequelae, especially memory disorders. Using a recovery model of West Nile virus (WNV) encephalitis, we show that, while macrophages deliver the antiviral and anti-neurogenic cytokine IL-1β during acute infection; viral recovery is associated with continued astrocyte inflammasome-mediated production of inflammatory levels of IL-1β, which is maintained by hippocampal astrogenesis via IL-1R1 signaling in neural stem cells (NSC). Accordingly, aberrant astrogenesis is prevented in the absence of IL-1 signaling in NSC, indicating that only newly generated astrocytes exert neurotoxic effects, preventing synapse repair and promoting spatial learning deficits. Ex vivo evaluation of IL-1β-treated adult hippocampal NSC revealed the upregulation of developmental differentiation pathways that derail adult neurogenesis in favor of astrogenesis, following viral infection. We conclude that NSC-specific IL-1 signaling within the hippocampus during viral encephalitis prevents synapse recovery and promotes spatial learning defects via altered fates of NSC progeny that maintain inflammation.
AB - Innate immune responses to emerging RNA viruses are increasingly recognized as having significant contributions to neurologic sequelae, especially memory disorders. Using a recovery model of West Nile virus (WNV) encephalitis, we show that, while macrophages deliver the antiviral and anti-neurogenic cytokine IL-1β during acute infection; viral recovery is associated with continued astrocyte inflammasome-mediated production of inflammatory levels of IL-1β, which is maintained by hippocampal astrogenesis via IL-1R1 signaling in neural stem cells (NSC). Accordingly, aberrant astrogenesis is prevented in the absence of IL-1 signaling in NSC, indicating that only newly generated astrocytes exert neurotoxic effects, preventing synapse repair and promoting spatial learning deficits. Ex vivo evaluation of IL-1β-treated adult hippocampal NSC revealed the upregulation of developmental differentiation pathways that derail adult neurogenesis in favor of astrogenesis, following viral infection. We conclude that NSC-specific IL-1 signaling within the hippocampus during viral encephalitis prevents synapse recovery and promotes spatial learning defects via altered fates of NSC progeny that maintain inflammation.
KW - Adult neural stem cell
KW - Astrogenesis
KW - Flavivirus encephalitis
KW - Interleukin-1
KW - Post-infectious cognitive dysfunction
KW - Spatial learning
KW - Synapse elimination
UR - http://www.scopus.com/inward/record.url?scp=85121975767&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2021.10.010
DO - 10.1016/j.bbi.2021.10.010
M3 - Article
C2 - 34695572
AN - SCOPUS:85121975767
SN - 0889-1591
VL - 99
SP - 383
EP - 396
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -