靶向平足蛋白调控小胶质细胞极化减轻脑出血后神经炎症机制研究

Target significance and inflammatory response mechanisms of podoplanin in the treatment of cerebral haemorrhage

摘要

通过生物信息学方法探讨了平足蛋白(podoplanin,PDPN)在实验性脑出血中的表达及其功能机制,以期为脑出血的治疗提供新的靶点和理论依据.首先,基于GSE216607数据集筛选出与脑出血相关的差异表达基因,并结合机器学习算法确定了3个核心基因:PDPN、Cdk2和Cxcl16.对这些基因进行了功能富集分析,评估其潜在的生物学通路.重点研究PDPN,构建脑出血动物模型,采用免疫印迹、qPCR、免疫组化及免疫荧光等方法验证PDPN在脑出血后小胶质细胞中的高表达,并探讨其信号通路.结果显示,PDPN在脑出血后小胶质细胞中表达显著上调,且使用PDPN抑制性单克隆抗体SZ168治疗后显著改善了小鼠的短期神经功能损伤和血肿情况,通过NF-κB通路的调控抑制小胶质细胞向促炎表型转化,并促进其向抑炎表型转化,减少炎症因子的释放.综上,PDPN通过调节小胶质细胞极化功能,参与了脑出血后的神经炎症反应,其作为潜在靶点为脑出血治疗提供了新的思路.

Abstract

In this study, we investigated the role of podoplanin (PDPN) in cerebral hemorrhage using bioinformatics and experimental approaches. Differentially expressed genes related to cerebral hemorrhage were identified from the GSE216607 dataset, and three core genes (PDPN, Cdk2, and Ccl16) were selected using machine learning algorithms. Functional enrichment analysis revealed their involvement in key biological pathways. Focusing on PDPN, we constructed a cerebral hemorrhage animal model and verified that PDPN expression was significantly up-regulated in microglia after hemorrhage. Treatment with the PDPN-inhibitory monoclonal antibody SZ168 improved neurological deficits and reduced hematomas in mice. Mechanistically, SZ168 inhibited microglial polarization toward a pro-inflammatory phenotype and promoted an anti-inflammatory phenotype by modulating the NF-κB pathway, thereby reducing inflammatory factor release. In conclusion, PDPN plays a critical role in neuroinflammation after cerebral hemorrhage by regulating microglial polarization, suggesting its potential as a therapeutic target for cerebral hemorrhage treatment.

关键词

脑出血 / 炎症反应 / 平足蛋白 / 小胶质细胞 / 生物信息学

Key words

cerebral haemorrhage / inflammation response / podoplanin / microglia / bioinformatics

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基金资助

国家自然科学基金(81873431)