RBM3 Promotes Anti-inflammatory Responses in Microglia and Serves as a Neuroprotective Target of Ischemic Stroke

Ischemic stroke is a major cause of death and disability in adults. Hypothermic treatment is successful in treating neonatal cerebral ischemia, but its application is restricted in adult patients due to complex management strategies and severe adverse effects. Two homologous RNA-binding proteins, RBM3 and CIRP, are the only known cold-inducible proteins in vertebrates, and their expression levels are robustly elevated by mild to moderate hypothermia. In previous studies, we and others have demonstrated that both RBM3 and CIRP mediate the neuroprotective and neurogenic effects of hypothermia in cell and animal models. However, CIRP can also be detrimental to neurons by triggering neuroinflammatory responses, complicating its post-stroke functions. In this study, we compared the properties of the two cold-inducible RNA-binding proteins after ischemic stroke. Our results indicated that RBM3 expression was stimulated in the ischemic brain of stroke patients, while CIRP expression was not. In an experimental model, RBM3 can ameliorate ischemic-like insult by promoting neuronal survival and eliciting anti-inflammatory responses in activated microglia, while the impact of CIRP was intriguing. Collectively, our data supported the notion that RBM3 may be a more promising therapeutic target than CIRP for treating ischemic stroke. We further demonstrated that zr17-2, a small molecule initially identified to target CIRP, can specifically target RBM3 but not CIRP in microglia. zr17-2 demonstrated anti-inflammatory and neuroprotective effects after ischemic stroke both in vitro and in vivo, suggesting its potential therapeutic value.