通过Wnt5a依赖矩阵金属蛋白酶-7和化细胞外囊释放调节CXCL4诱导的PBMC
Jona B Krohn1,2, Laurine Kristin Sprehe1,2, Florian Sicklinger1,2
1Department of Cardiology, Pulmonology and Angiology, University Hospital Heidelberg, Germany. (J.B.K., L.K.S., F.S., J.K., C.H., C.A.G., H.A.K., N.F., F.L.).
Arteriosclerosis, thrombosis, and vascular biology
|August 21, 2025
概括
化学物质CXCL4 (化学物质[C-X-C动机]配体4) 诱导促炎单细胞,促进血管化. 这些单细胞释放了富含MMP7和S100A8的细胞外囊泡,推动了基质重塑和炎症.
科学领域:
- 心血管生物学
- 免疫学
- 细胞外基质生物学
背景情况:
- 在血管炎症中,巨细胞异质性至关重要.
- 化学物质CXCL4 (化学物质[C-X-C动机]配体4) 驱动一种与动脉样硬化斑块不稳定相关的单细胞/巨类表型.
- 诱导CXCL4的巨细胞显示S100A8 (S100结合蛋白A8) 和MMP7 (矩阵金属蛋白酶-7) 的表达增加,但潜在的机制尚不清楚.
研究的目的:
- 研究CXCL4诱导的单细胞介导血管炎症的机制.
- 描述CXCL4分化的单细胞及其细胞外囊 (EV) 的表型和功能.
- 确定Wnt途径在CXCL4诱导的单细胞反应和血管化的作用.
主要方法:
- 斑块巨细胞的单细胞RNA测序
- 用CXCL4区分人类外围血液衍生单细胞 (PBMC).
- 分析骨质的特征和化电流释放.
- 研究Wnt路径的关联.
- 在体外评估EV化潜力和对血管光滑肌细胞的炎症作用.
- 在人类动脉斑块中进行组织学验证.
主要成果:
- 单细胞测序发现了具有炎症特征的斑块巨细胞的CXCL4敏感亚群.
- 在CXCL4区分的PBMC中,S100A8,MMP7和骨质标志物呈上升调节,释放富含MMP7,S100A8,Anx5和ALP的EV.
- 在体外,CXCL4诱导的PBMC及其EV促进了细胞外基质 (ECM) 化.
- Wnt5a- CaMKII信号轴与CXCL4诱导的骨质生态表型,EV化和MMP7/ S100A8丰富相关.
- 在血管光滑肌细胞中刺激炎症基因表达.
- 人类动脉斑块显示出CXCL4诱导的巨细胞丰富性,Wnt5a- CaMKII激活和化.
结论:
- 鉴定出一种由单细胞介导的ECM重塑的新机制.
- Wnt5a-CaMKII信号激活了由CXCL4诱导的促炎单细胞分泌的MMP7+/ S100A8+化EVs.
- 这一过程有助于血管炎症和动脉样硬化斑块的化.
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