TRIM21 Exacerbates Ischemic Brain Injury by Promoting Astrocyte-Mediated Neuroinflammation via K63-Linked...

The pathophysiology of ischemic stroke is critically mediated by detrimental neuroinflammation. Tripartite motif-containing 21 (TRIM21) serves as an E3 ubiquitin ligase that regulates important biological functions. Nonetheless, the specific role of TRIM21 in neuroinflammation and ischemic brain injury remains unclear. In this study, we found that TRIM21 expression was up-regulated in astrocytes within the peri-infarct regions of mice subjected to transient middle cerebral artery occlusion (tMCAO) and in an in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model. TRIM21 deficiency alleviated cerebral ischemia/reperfusion (I/R) injury by attenuating the inflammatory responses and oxidative stress. Mechanistically, our findings demonstrated that TRIM21 interacts with MDA5 and sequentially promotes the K63-linked ubiquitination and stabilization of MDA5, ultimately activating the nuclear factor κB (NF-κB) pathway in astrocytes. Moreover, MDA5 overexpression effectively reversed protective effects of TRIM21 deficiency after cerebral ischemia. Consistently, brain-targeted TRIM21 silencing with nanoparticle delivery considerably ameliorated cerebral I/R injury. Collectively, our findings identify TRIM21 as a novel astrocyte-specific mediator of neuroinflammation in cerebral ischemic injury and highlight its potential as a therapeutic target for ischemic stroke.