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TRIM9-mediated resolution of neuroinflammation confers neuroprotection upon ischemic stroke in mice

Authors: 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

Summary:

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.

Source: Cell Reports, 2019; 27 (2): 549