Abstract
Excessive and unresolved neuroinflammation is a key component of the pathological cascade in brain injuries such as ischemic stroke. Tripartite motif-containing 45 (TRIM45) is a ubiquitin E3 ligase involved in various critical biological processes. However, the role of TRIM45 in cerebral ischemia remains unknown. Here, we found that the TRIM45 protein was highly expressed in the peri-infarct areas of mice subjected to cerebral ischemia and reperfusion injury induced by middle cerebral artery occlusion. This study systemically evaluated the putative role of TRIM45 in the regulation of neuroinflammation during ischemic injury and the potential underlying mechanisms. We found that TRIM45 knockdown significantly decreased proinflammatory cytokine and chemokine production in primary cultured microglia challenged with oxygen-glucose deprivation and reoxygenation (OGD/R) treatment. Mechanistically, we demonstrated that TRIM45 constitutively interacted with TAB2 and consequently facilitated the Lys-63-linked polyubiquitination of TAB2, leading to the formation of the TAB1–TAK1–TAB2 complex and activation of TAK1, which was ultimately followed by activation of the nuclear factor-kappa B (NF-κB) signaling pathway. In an in vitro coculture Transwell system, downregulation of TRIM45 expression also inhibited the OGD/R-induced activation of microglia and alleviated neuronal apoptosis. More importantly, microglia-specific knockdown of TRIM45 in mice significantly reduced the infarct size, mitigated neurological deficit scores, and improved cognitive function after ischemic stroke. Taken together, our study reveals that the TRIM45–TAB2 axis is a crucial checkpoint that controls NF-κB signaling in microglia during cerebral ischemia and reperfusion injury. Therefore, targeting TRIM45 may be an attractive therapeutic strategy.
Highlights
Cerebral ischemia is a widespread leading cause of death and disability, and it is mainly caused by decreased blood flow to the brain and results in brain tissue damage[1]
Tripartite motif-containing 45 (TRIM45) expression in microglia is upregulated after ischemic stroke To evaluate the role of TRIM45 in cerebral I/R injury, we examined
TRIM45 promotes the association of TAK1 and TAB2 based on its E3 ligase activity As the RING domain of TRIM45 is crucial for its function[38], we explored whether TRIM45 exerts its function via its E3 ligase activity
Summary
Cerebral ischemia is a widespread leading cause of death and disability, and it is mainly caused by decreased blood flow to the brain and results in brain tissue damage[1]. Gene expression in damaged neurons is rapidly changed, and multiple factors, such as ATP and glutamic acid, are produced, which stimulate the activation and migration of nearby microglia to protect the brain from ischemic stroke[8]. The excessive production of inflammatory cytokines can exacerbate damage to neighboring neurons and result in delayed deterioration of ischemic tissue[9,10]. The identification of pivotal regulators that target these signaling molecules and attenuate the production of inflammatory factors by microglia would prevent neuronal death after ischemic stroke
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