Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Neurosurgery, Jiangsu Province Hospital, Nanjing, China.
FASEB J. 2024 Sep 15;38(17):e70016. doi: 10.1096/fj.202401117R.
Traumatic brain injury (TBI), which is characterized by acute neurological dysfunction, is also one of the most widely recognized environmental risk factors for various neurological and psychiatric disorders. However, the role of TBI in neurological perturbation and the mechanisms underlying these disorders remain unknown. We evaluated transcriptional changes in cells of the frontal cortex after TBI by exploiting single-cell RNA sequencing (scRNA-Seq). We adopted the gene expression omnibus and scRNA-Seq to identify the mediation by secretogranin II (SCG2) of TBI-induced schizophrenia. Astrocytes are a principal source of SCG2 in the frontal cortex after TBI. Our analysis indicated that SCG2-triggered disruption of the blood-brain barrier (BBB) via the CypA-MMP-9 signaling pathway. Furthermore, astrocytic SCG2 knockout in the frontal cortex reduced BBB damage, mitigated inflammation, and inhibited schizophrenia after TBI. In conclusion, we identified the SCG2-CypA-MMP-9 signaling pathway in reactive astrocytes as a key switch in the protection of the BBB and provided a novel therapeutic avenue for treating psychiatric disorders after TBI.
创伤性脑损伤（TBI）的特征是急性神经功能障碍，也是各种神经和精神疾病公认的最广泛的环境风险因素之一。然而，TBI 在神经紊乱中的作用以及这些疾病的潜在机制尚不清楚。我们通过单细胞 RNA 测序（scRNA-Seq）来评估 TBI 后额叶皮质细胞中的转录变化。我们采用基因表达组学和 scRNA-Seq 来确定分泌颗粒蛋白 II（SCG2）在 TBI 诱导的精神分裂症中的介导作用。星形胶质细胞是 TBI 后额叶皮质中 SCG2 的主要来源。我们的分析表明，SCG2 通过 CypA-MMP-9 信号通路触发血脑屏障（BBB）的破坏。此外，额叶皮质中星形胶质细胞的 SCG2 敲除减少了 BBB 损伤、减轻了炎症，并抑制了 TBI 后的精神分裂症。总之，我们确定了反应性星形胶质细胞中的 SCG2-CypA-MMP-9 信号通路是保护 BBB 的关键开关，并为治疗 TBI 后的精神疾病提供了新的治疗途径。
