TRIM62 knockout protects against cerebral ischemic injury in mice by suppressing NLRP3-regulated neuroinflammation.

Cerebral stroke is a leading global cause for mortality and disability. However, its pathogenesis is still unclear. Most tripartite motif (TRIM) family proteins, including TRIM62, have E3 ubiquitin ligase activities, and have multiple functions in regulating cellular processes. Nevertheless, the effects of TRIM62 on cerebral stroke still remain vague. Here, we reported that TRIM62 expression was markedly up-regulated in oxygen and glucose deprivation (OGD)-treated microglial cells. After cerebral ischemia, significantly elevated expression of TRIM62 was detected in peri-infarct area of wild type (WT) mice. The TRIM62 knockout (KO) mice exhibited alleviated apoptosis and neuroinflammation in the ischemic brain, eventually attenuating the stroke outcomes. Both in vitro and in vivo studies showed that nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome was dramatically activated in cerebral ischemia/reperfusion (I/R) conditions, while being ameliorated in TRIM62-KO mice, contributing to the suppression of neuroinflammatory response. Importantly, the in vitro experiments showed that OGD could induce the K63-ubiquitination of TRIM62 and the interaction between TRIM62 and NLRP3. In addition, adenovirus-regulated TRIM62 over-expression promoted the NLRP3 and nuclear factor κB (NF-κB) signaling, along with elevated interleukin-1β (IL-1β) and IL-18 transcriptional activities. Together, our results demonstrated that TRIM62 suppression was strongly protective in ischemic stroke through inhibiting NLRP3-regulated neuroinflammation.