NR4A1 regulates cerebral ischemia-induced brain injury by regulating neuroinflammation through interaction with NF-κB/p65.

Stroke is reported as a leading cause of mortality and disability in the world. Neuroinflammation is significantly induced responding to ischemic stroke, and this process is accompanied with microglial activation. However, the pathogenesis contributing to ischemic stroke remains unclear. NR4A1 (Nur77) is a nuclear receptor that is expressed in macrophages, playing a significant role in regulating inflammatory response. In the present study, we attempted to explore the effects of NR4A1 on ischemic stroke using in vivo and in vitro studies. Results suggested that NR4A1 expression in microglia was markedly increased after cerebral ischemic damage. Then, we found that NR4A1 knockout attenuated ischemia-triggered infarction volume and neuron injury. Also, cognitive impairments were improved in ischemic mice with NR4A1 deficiency, resulting in functional improvements. Moreover, M1 polarization in microglia and neutrophil recruitment was significantly alleviated by NR4A1 deletion, as evidenced by the reduced expression of M1 markers, chemokines, as well as intracellular adhesion molecule-1 (ICAM-1) and myeloperoxidase (MPO) levels. Importantly, we found that NR4A1 could interact with nuclear factor-κB (NF-κB)/p65 based on in vivo and in vitro results. Suppressing p65 activation by the use of its inhibitor clearly reduced the NR4A1 expression, M1 polarization and neutrophil recruitments, while rescued the expression of anti-inflammatory factors in microglia treated with oxygen-glucose deprivation (OGD). Therefore, NR4A1 suppression in microglia restrained neuroinflammation through interacting with NF-κB/p65 to attenuate ischemic stroke.