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| Status |
Public on Dec 31, 2018 |
| Title |
TRIM9-mediated resolution of neuroinflammation confers neuroprotection against ischemic stroke in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Excessive and unresolved neuroinflammation is part of the pathological cascade in brain injuries such as acute ischemia, as well as neurodegenerative diseases, including multiple sclerosis and Alzheimer’s disease. Particularly, timely resolution of inflammation is critical for the recovery and repair after brain injury. The nuclear factor-κB (NF-κB) signaling plays a central role in neuroinflammation through transcriptional induction of proinflammatory genes. Here, we report that TRIM9, a brain-specific member of the TRIpartite motif (TRIM) family with ubiquitin E3 ligase activity, is upregulated in the peri-infarct cortical areas of mouse brain upon ischemic stroke, and governs the resolution of NF-κB-mediated neuroinflammation. Mechanistically, neuronal TRIM9 sequestered β-TrCP, a component of the Skp-Cullin-F-box (SCF) E3 ligase complex, from ubiquitinating IκBα, thereby mitigating NF-κB-dependent inflammatory responses including production of proinflammatory mediators and infiltration of immune cells. Consequently, Trim9 deficient mice were highly vulnerable to ischemia, manifesting uncontrolled neuroinflammation and exacerbated neuropathological and neurological outcomes. Systemic administration of recombinant adeno-associated virus (AAV)-PHP.B, allowing brain-wide enriched TRIM9 expression, effectively resolved neuroinflammation and alleviated neuronal death in aging mice. This reveals that TRIM9 is essential for fine tuning of NF-κB-dependent neuroinflammation, and TRIM9-potentiation based therapy may offer a new approach for the treatment of stroke and inflammation-related neurological disorders.
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| Overall design |
RNA-seq
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| Contributor(s) |
Zeng J, Wang Y, Luo Z, Chang L, Xie X, Duan S, Wang Q, Deverman BE, Gradinaru V, Gupton SL, Zlokovic BV, Zhao Z, Jung JU |
| Citation(s) |
30970257 |
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| Submission date |
May 18, 2018 |
| Last update date |
May 09, 2019 |
| Contact name |
Zhifei Luo |
| E-mail(s) |
Zhifeilu@usc.edu
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| Organization name |
University of Southern California
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| Street address |
1450 Biggy Street, NRT 6514
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90089-9601 |
| Country |
USA |
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| Platforms (1) |
| GPL21493 |
Illumina HiSeq 3000 (Mus musculus) |
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| Samples (5)
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| Relations |
| BioProject |
PRJNA472064 |
| SRA |
SRP148460 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE114652_trim9_sham_stroke.txt.gz |
1.3 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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