TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice
Creators
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1.
University of Southern California
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2.
California Institute of Technology
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3.
University of North Carolina at Chapel Hill
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.
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.Attached Files
Published - 1-s2.0-S2211124718319855-main.pdf
Accepted Version - nihms-1526692.pdf
Supplemental Material - 1-s2.0-S2211124718319855-mmc1.pdf
Files
1-s2.0-S2211124718319855-main.pdf
Additional details
Additional titles
- Alternative title
- TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotectionupon Ischemic Stroke in Mice
Identifiers
- PMCID
- PMC6485958
- Eprint ID
- 94579
- Resolver ID
- CaltechAUTHORS:20190409-100816489
Funding
- NIH
- CA200422
- NIH
- CA180779
- NIH
- DE023926
- NIH
- DE027888
- NIH
- DE28521
- NIH
- AI073099
- NIH
- AI116585
- NIH
- AI129496
- NIH
- AI140718
- NIH
- AI140705
- Hastings Foundation
- Fletcher Jones Foundation
- NIH
- 9R01NS090904-16
- Alzheimer's Association
- NIRG-15-363387
- Whittier Foundation
- Cure for Alzheimer's Fund
- NS090904
- Foundation Leducq Translatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease
- 16 CVD 05
- NIH
- GM108970
- Caltech Beckman Institute
- Heritage Medical Research Institute
- NIH
- DP20D017782
Dates
- Created
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2019-04-09Created from EPrint's datestamp field
- Updated
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2022-03-01Created from EPrint's last_modified field
Caltech Custom Metadata
- Caltech groups
- Heritage Medical Research Institute