在中性粒细胞和神经元中,cathelicidin抗微生物的表达对抗性地调节神经炎症
Subash Chand Verma1, Emmanuelle Enée1, Kanchanadevi Manasse1
1Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, Paris, France.
The Journal of clinical investigation
|December 10, 2024
概括
与cathelicidin相关的抗微生物 (CRAMP) 在多发性硬化症 (MS) 发病过程中具有双重作用. 早期的CRAMP促进疾病,而晚期的神经CRAMP提供保护和治疗潜力.
科学领域:
- 神经免疫学 神经免疫学
- 分子医学是分子医学.
- 自免疫性疾病 自免疫性疾病
背景情况:
- 多发性硬化症 (MS) 是中枢神经系统 (CNS) 的一种慢性自身免疫性疾病,其病理生理学不明确,并且没有治愈方法.
- 抗微生物 (AMP),包括与cathelicidin相关的AMP (CRAMP),具有免疫调节作用,存在于中枢神经系统.
研究的目的:
- 为了研究CRAMP在实验性自身免疫脑膜炎 (EAE) 中的作用,MS的小鼠模型.
- 阐明CRAMP影响神经炎症和疾病进展的机制.
主要方法:
- 利用EAE小鼠模型研究CRAMP对疾病发病和严重性的影响.
- 研究了CRAMP对免疫细胞激活 (中性粒细胞,树突细胞,微质细胞,星球细胞) 和细胞因子产生的影响.
- 研究了信号通路 (cGAS/STING,FPR2,FFAR2/3) 的作用和丁酸盐的作用.
主要成果:
- 早期中枢神经系统招募的中性粒细胞产生了富含CRAMP的中性粒细胞细胞外陷 (NETs),这对于EAE启动至关重要.
- 与NET相关的CRAMP通过cGAS/STING通路通过树突细胞的IL-6产生促进了Th17反应.
- 后来,神经CRAMP降低了EAE的严重程度;CRAMP1-39通过FPR2调节了微质/星细胞激活.
- 丁酸盐的使用通过FFAR2/3增加了神经CRAMP,从而防止EAE.
结论:
- 根据其细胞源和疾病阶段,CRAMP在MS的发病过程中表现出相反的作用.
- 早期来自中性粒细胞的CRAMP会加剧神经炎症,而后来的来自神经元的CRAMP则具有神经保护作用.
- 向CRAMP或调节其产生 (例如,通过丁酸盐) 为MS和其他神经炎症疾病提供了治疗途径.
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