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TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice

Zeng, Jianxiong and Wang, Yaoming and Luo, Zhifei and Chang, Lin-Chun and Yoo, Ji Seung and Yan, Huan and Choi, Younho and Xie, Xiaochun and Deverman, Benjamin E. and Gradinaru, Viviana and Gupton, Stephanie L. and Zlokovic, Berislav V. and Zhao, Zhen and Jung, Jae U. (2019) TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice. Cell Reports, 27 (2). pp. 549-560. ISSN 2211-1247. PMCID PMC6485958. https://resolver.caltech.edu/CaltechAUTHORS:20190409-100816489

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Abstract

Excessive and unresolved neuroinflammation is a key component of the pathological cascade in brain injuries such as ischemic stroke. Here, we report that TRIM9, a brain-specific tripartite motif (TRIM) protein, was highly expressed in the peri-infarct areas shortly after ischemic insults in mice, but expression was decreased in aged mice, which are known to have increased neuroinflammation after stroke. Mechanistically, TRIM9 sequestered β-transducin repeat-containing protein (β-TrCP) from the Skp-Cullin-F-box ubiquitin ligase complex, blocking IκBα degradation and thereby dampening nuclear factor κB (NF-κB)-dependent proinflammatory mediator production and immune cell infiltration to limit neuroinflammation. Consequently, Trim9-deficient mice were highly vulnerable to ischemia, manifesting uncontrolled neuroinflammation and exacerbated neuropathological outcomes. Systemic administration of a recombinant TRIM9 adeno-associated virus that drove brain-wide TRIM9 expression effectively resolved neuroinflammation and alleviated neuronal death, especially in aged mice. These findings reveal that TRIM9 is essential for resolving NF-κB-dependent neuroinflammation to promote recovery and repair after brain injury and may represent an attractive therapeutic target.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.celrep.2018.12.055DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485958PubMed CentralArticle
ORCID:
AuthorORCID
Deverman, Benjamin E.0000-0002-6223-9303
Gradinaru, Viviana0000-0001-5868-348X
Zlokovic, Berislav V.0000-0002-6802-8232
Additional Information:© 2018 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Received 13 May 2018, Revised 26 August 2018, Accepted 12 December 2018, Available online 9 April 2019. This research was supported in part by the NIH (grants CA200422, CA180779, DE023926, DE027888, DE28521, AI073099, AI116585, AI129496, AI140718, and AI140705), the Hastings Foundation, and the Fletcher Jones Foundation (J.U.J.); NIH grant 9R01NS090904-16 (B.V.Z.); the Alzheimer's Association (grant NIRG-15-363387) and Whittier Foundation (Z.Z.); the Cure for Alzheimer's Fund (B.V.Z. and Z.Z.), NS090904, and Foundation Leducq Translatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease (reference 16 CVD 05) (B.V.Z.); and GM108970 (S.L.G.). We acknowledge funding from the Beckman Institute at Caltech (to V.G. and B.E.D.) through the Resource Center for CLARITY, Optogenetics, and Vector Engineering. V.G. is a Heritage Principal Investigator supported in this work by an NIH Director’s New Innovator Award (DP20D017782 to V.G.). Author Contributions: J.Z., Z.Z., and J.U.J. designed all experiments, analyzed data, and wrote the paper; J.Z., Y.W., and Z.L. performed experiments and analyzed data, and L.-C.C., J.S.Y., H.Y., Y.C., and X.X. performed experiments. B.E.D., V.G., S.L.G., and B.V.Z. contributed key materials, provided guidance for some experiments, and edited the paper. The authors declare no competing interests.
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
NIHCA200422
NIHCA180779
NIHDE023926
NIHDE027888
NIHDE28521
NIHAI073099
NIHAI116585
NIHAI129496
NIHAI140718
NIHAI140705
Hastings FoundationUNSPECIFIED
Fletcher Jones FoundationUNSPECIFIED
NIH9R01NS090904-16
Alzheimer's AssociationNIRG-15-363387
Whittier FoundationUNSPECIFIED
Cure for Alzheimer's FundNS090904
Foundation Leducq Translatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease16 CVD 05
NIHGM108970
Caltech Beckman InstituteUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
NIHDP20D017782
Subject Keywords:TRIM9; stroke; neuroinflammation; NF-κB
Issue or Number:2
PubMed Central ID:PMC6485958
Record Number:CaltechAUTHORS:20190409-100816489
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190409-100816489
Official Citation:Jianxiong Zeng, Yaoming Wang, Zhifei Luo, Lin-Chun Chang, Ji Seung Yoo, Huan Yan, Younho Choi, Xiaochun Xie, Benjamin E. Deverman, Viviana Gradinaru, Stephanie L. Gupton, Berislav V. Zlokovic, Zhen Zhao, Jae U. Jung, TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice, Cell Reports, Volume 27, Issue 2, 2019, Pages 549-560.e6, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2018.12.055. (http://www.sciencedirect.com/science/article/pii/S2211124718319855)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94579
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Apr 2019 18:12
Last Modified:03 Oct 2019 21:05

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