S1PR3/RhoA signaling pathway in microglia mediates inflammatory activation in early brain injury after subarachnoid hemorrhage

Abstract Spontaneous subarachnoid hemorrhage (SAH) is a serious and common cerebrovascular disease with high mortality rate and poor prognosis. The immune response caused by abnormal activation of intracranial microglia is one of the main factors contributing to early brain injury after SAH. Sphingosine 1-phosphate (S1P) signaling pathway is widely involved in immune regulation, nerve cell differentiation and other processes. It has been reported that S1P expression is increased in cerebrospinal fluid after SAH, but its role in early brain injury and neuroinflammation induced by SAH remains unclear. In the rat model of SAH established by arterial puncture, low (0.5mg/kg) or high dose (5mg/kg) of the S1P receptor inhibitor FTY720 was administered immediately or at 24 hours after surgery. Improvement of behavioral scores and brain edema symptoms after SAH was observed in immediate treatment group at high dose. In addition, activation of cortical microglia near the perforation site was observed after SAH, and this activation was significantly inhibited after 5mg/kg FTY720 treatment immediately after surgery. Further studies showed that S1P could induce activation and M1 polarization of human microglia cells in vitro. This activation may be mediated through the S1PR3-Gα12/13-RhoA pathway. Therefore, our study highlights the important role of S1P signaling and microglia activation in SAH-induced early brain injury, and provides evidence for novel therapies targeting the neuroinflammatory process after SAH.