Induced neural stem cells regulate microglial activation through Akt-mediated upregulation of CXCR4 and Crry in a mouse model of closed head injury

Abstract

Abstract Microglial activation that occurs rapidly after closed head injury (CHI) may play important and complex roles in the process of neuroinflammation-associated neuronal damage and repair. We previously reported that induced neural stem cells (iNSCs) have the potential to modulate the behaviour of activated microglia via CXCL12/CXCR4 signalling, influencing their activation such that they can promote neurological recovery. However, the mechanism of CXCR4 upregulation in iNSCs remains unclear. In this study, we found that NF-κB activation induced by CHI mouse serum in microglia promoted CXCL12 and TNF-α expression but suppressed IGF-1 expression. However, CR2-Crry reduced the effects of CHI mouse serum-induced NF-κB activation in microglia and the levels of activated microglia as well as CXCL12 and TNF-α. Additionally, we observed that iNSCs can receive stimulation (including CXCL12 secreted by activated microglia) and upregulate the levels of CXCR4 and Crry via the interplay among CXCL12/CXCR4, Crry and Akt signalling to modulate microglial activation. In agreement with the in vitro experimental results, Akt activation enhanced the immunoregulatory effects of iNSC grafts on microglial activation leading to the promotion of neurological recovery via IGF-1 secretion and the neuroprotective effects of iNSC grafts through CXCR4 and Crry upregulation in the injured cortices of CHI mice. Notably, these beneficial effects of Akt activation in iNSCs were positively correlated with the therapeutic effects of iNSCs on neuronal injury, cerebral oedema and neurological disorders post-CHI.