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

Publication date: 9 April 2019Source: Cell Reports, Volume 27, Issue 2Author(s): 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. JungSummaryExcessive 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 reco...
Source: Cell Reports - Category: Cytology Source Type: research