细胞内C5a-mtC5aR1轴通过DRP1-介导的线粒体功能障碍促进干眼的亡
Limei Wang1,2, Haijing Yan1,3, Yetao Shen1,2
1Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Zhejiang, China.
Investigative ophthalmology & visual science
|February 18, 2026
概括
这项研究表明,C5a-线粒体C5a受体1 (mtC5aR1) 途径驱动干眼 (DE) 中的角膜细胞损伤. 在小鼠模型中,用JPE-1375抑制mtC5aR1可降低炎症并保护DE.
科学领域:
- 眼科医生 眼科 眼科
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
背景情况:
- 干眼 (DE) 是一种复杂的眼睛表面疾病,其特征是炎症和上皮损伤.
- 线粒体功能障碍和氧化应激涉及DE的发病,但角膜上皮细胞损伤的确切机制尚未完全理解.
- 研究了补充系统成分C5a及其受体C5aR1在DE期间角膜上皮细胞的线粒体中的作用.
研究的目的:
- 研究C5a-线粒体C5a受体1 (mtC5aR1) 轴在干眼 (DE) 发病过程中在人类角膜上皮细胞 (HCEC) 中的作用.
- 阐明通过这种途径调解的角膜上皮细胞损伤的机制.
- 评估针对DE治疗这一轴的治疗潜力.
主要方法:
- 在正常和高位压力条件下检查了HCEC中的C5aR1表达和局部化.
- 使用药理抑制剂 (JPE-1375,PMX-53) 评估了细胞内C5a-mtC5aR1轴的功能作用.
- 分析了下游的信号通路,包括RIPK3 / MLKL介导的亡,DRP1激活,线粒体功能和炎症性细胞因子产生.
- 在DE小鼠模型中评估了JPE-1375的治疗疗效.
主要成果:
- 证明HCECs在外层线粒体膜 (mtC5aR1) 上表达C5aR1,在DE条件下表达上调.
- 显示,超的压力激活mtC5aR1,导致DRP1-介导的线粒体功能障碍和RIPK3/MLKL依赖性亡.
- 证实,用JPE-1375对mtC5aR1的药理学阻断显著减轻了亡,恢复了线粒体功能,并减少了在压力高的HCEC中炎症性细胞因子的产生.
- 观察到,在DE小鼠模型中,JPE-1375治疗减轻了角膜上皮损伤和炎症.
结论:
- 鉴定了细胞内C5a-mtC5aR1-DRP1轴作为驱动干眼疾病死亡的新机制.
- 针对mtC5aR1通路提供了一种潜在的治疗策略,以缓解DE的炎症和角膜损伤.
- 这项研究为底层DE病原体的分子机制提供了新的见解,并提出了一个有前途的治疗点.
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