原始识别复合体子单元6 (ORC6) 是LPS诱导的NFκB激活和促炎反应的关键调解者
Zichen Xie1, Haisu Lu1, Jiayi Zheng1
1Emergency Department, Minhang Hospital, Fudan University, Shanghai, China.
Cell communication and signaling : CCS
|August 14, 2024
概括
原始识别复合体子单元6 (ORC6) 对于与败血症相关的炎症至关重要. 沉默ORC6降低了促炎性细胞因子,并防止了感染性休克,这表明ORC6是治疗点.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 败血症是一种危及生命的疾病,由脂聚糖 (LPS) 激活的炎症反应驱动.
- 巨细胞和单细胞是参与败血症发病的关键免疫细胞.
- 了解调节这些反应的分子机制对于开发有效疗法至关重要.
研究的目的:
- 调查LPS诱导的巨细胞和单细胞的炎症反应中的原产地识别复合体子单元6 (ORC6) 的作用.
- 阐明ORC6影响这些反应的分子机制,特别是核因子kappa B (NFκB) 信号通路.
- 评估针对性ORC6在败血症小鼠模型中的治疗潜力.
主要方法:
- 在THP-1巨细胞,PBMC和BMDM中使用shRNA抑制ORC6.
- 在THP-1巨细胞中的CRISPR/Cas9介导的ORC6淘汰 (KO).
- 在THP-1巨细胞中ORC6的异宫过度表达.
- 评估促炎性细胞因子 (IL-1β,TNF-α,IL-6) 的表达和产生.
- 对NFκB信号通路激活的分析,包括p65与ORC6.6的相互作用.
- 在体内研究使用小鼠模型的LPS诱导的败血症休克与巨细胞特定的ORC6敲击.
主要成果:
- ORC6沉默显著降低了LPS诱导的IL-1β,TNF-α和IL-6的表达和产生.
- ORC6 KO抑制了LPS诱导的炎症反应,而ORC6过度表达则增强了它们.
- ORC6对于LPS诱导的NFκB激活至关重要,调解ORC6和核p65.5之间的相互作用.
- 由dRNA和HMGB1.1诱导的ORC6枯竭抑制了NFκB激活.
- 巨细胞特异性ORC6敲击保护小鼠免受LPS诱导的败血症休克和减少血清促炎细胞因子.
结论:
- ORC6在调解LPS诱导的NFκB激活和败血症的炎症反应中发挥着关键作用.
- ORC6是巨细胞和单细胞中炎症信号的关键调节者.
- 向ORC6代表了对败血症和相关炎症状况的潜在新疗法策略.
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