TRIM45 causes neuronal damage by aggravating microglia-mediated neuroinflammation upon cerebral ischemia and reperfusion injury

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.

Sirtuin 5 aggravates microglia-induced neuroinflammation following ischaemic stroke by modulating the desuccinylation of Annexin-A1

“…The spatial learning and memory of the mice were determined by the MWM test as described previously [ 34 ]. Briefly, the water maze consists of a circular tank with a diameter of 120 cm and a circular platform with a diameter of 6 cm.…”

SENP6 induces microglial polarization and neuroinflammation through de-SUMOylation of Annexin-A1 after cerebral ischaemia–reperfusion injury

“…Then, we investigated the protective effects of SENP6 knockdown on cerebral ischaemia in vivo. First, we applied an adeno-associated virus type 2/6 (AAV2/6)-mediated approach to knockdown SENP6 in microglia in the brains of ischaemic mice [ 19 , 20 , 24 ]. For this, we constructed AAV2/6, which expresses shRNA only in cells expressing Cre recombinase (Fig.…”

“…The intraluminal filament technique was used to induce focal cerebral ischaemia through the transient occlusion of the middle cerebral artery as we reported previously [ 20 ]. In brief, mice were anaesthetized using chloral hydrate (350 mg/kg, i.p.).…”

“…Plasmids were constructed as we previously described [ 20 ]. PCR technology was used to amplify the full-length DNA segment ANXA1 and SUMO2 coding sequences, which were cloned into HA-tagged pcDNA 3.0 (HA-ANXA1) and Myc-pcDNA 3.0 (Myc-SUMO2), respectively.…”

Emerging Roles of TRIM Family Proteins in Gliomas Pathogenesis

“…Specifically, it was demonstrated that TRIM45 regulates cerebral I/R injury by activating NF-κB signaling in microglia through interaction with TAB2, consequently leading to neuronal apoptosis. Knockdown of TRIM45 has proved to provide striking results for the above effects by inhibiting the inflammatory response [ 72 ].…”