细胞外CIRP促进Kupffer细胞在败血症中的炎症两极化
Junji Shimizu1, Atsushi Murao1, Yongchan Lee1
1Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States.
Frontiers in immunology
|June 17, 2024
概括
细胞外冷诱导性RNA结合蛋白 (eCIRP) 在败血症中通过TLR4通路驱动Kupffer细胞M1极化. 这导致炎症和器官损伤的增加,这表明eCIRP是潜在的治疗点.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 病理生理学 病理生理学
背景情况:
- 败血症涉及宿主对感染的反应失调,导致炎症和器官损伤.
- 细胞外冷诱导性RNA结合蛋白 (eCIRP) 是一种与损伤相关的分子模式,与败血症诱导的炎症和损伤有关.
- 库弗弗细胞,肝脏的常驻巨细胞,可以采用炎症M1表型,加剧败血症病理.
研究的目的:
- 调查eCIRP在促进毒症期间Kupffer细胞M1极化中的作用.
- 阐明信号通路,特别是参与eCIRP介导的Kupffer细胞激活的Toll-like受体4 (TLR4).
- 评估针对eCIRP的治疗潜力,以调节败血症中库普费尔细胞表型.
主要方法:
- 来自野生类型 (WT) 和TLR4缺乏 (TLR4-/-) 的小鼠的库弗尔细胞被用重组小鼠eCIRP刺激.
- 使用ELISA测量了促炎性细胞因子水平 (IL-6,TNFα).
- 通过定量PCR (qPCR) 来评估M1 (iNOS) 和M2 (CD206) 标记物的信使RNA (mRNA) 表达.
- 在WT和eCIRP缺陷 (CIRP-/-) 的小鼠中,通过结和穿孔 (CLP) 诱导败血症,随后进行库普费尔细胞标记物的流动细胞计分析.
主要成果:
- 根据eCIRP的剂量和时间,从WT库弗弗细胞中增加了IL-6和TNFα的释放,这种效应在TLR4-/-细胞中被取消.
- eCIRP显著上调了WT库普弗细胞中的iNOS (M1标记物) mRNA表达,TLR4-/-细胞的反应减少.
- 在体内,与CIRP-/-小鼠相比,在WT败血症小鼠中,库普弗细胞中的iNOS表达显著增加.
- 库普费尔细胞的M1/M2极化比在WT败血症小鼠中显著增加,但在CIRP-/-小鼠中没有.
结论:
- 在败血症的背景下,eCIRP通过TLR4信号通路诱导Kupffer细胞M1极化.
- 这种eCIRP驱动的M1两极化导致炎症性细胞因子的过度产生,导致败血症病理.
- 向eCIRP是一个有希望的治疗策略,通过防止Kupffer细胞M1极化来缓解败血症引起的炎症.
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