Other
14 Authors
- Choi Y,
- Yan H,
- Wang Y,
- Yoo JS,
- Xie X,
- Gradinaru V,
- Jung JU,
- Chang LC,
- Zeng J,
- Deverman BE,
- Zlokovic BV,
- Zhao Z,
- Luo Z,
- Gupton SL
| First Author | Zeng J | Year | 2019 |
| Journal | Cell Rep | Volume | 27 |
| Issue | 2 | Pages | 549-560.e6 |
| PubMed ID | 30970257 | Mgi Jnum | J:284411 |
| Mgi Id | MGI:6381101 | Doi | 10.1016/j.celrep.2018.12.055 |
| Citation | Zeng J, et al. (2019) TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice. Cell Rep 27(2):549-560.e6 |
| abstractText | 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 beta-transducin repeat-containing protein (beta-TrCP) from the Skp-Cullin-F-box ubiquitin ligase complex, blocking IkappaBalpha degradation and thereby dampening nuclear factor kappaB (NF-kappaB)-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-kappaB-dependent neuroinflammation to promote recovery and repair after brain injury and may represent an attractive therapeutic target. |
