巨细胞的RAGE激活在NASH中具有预炎性作用
Gopanandan Parthasarathy1, Amy S Mauer1, Naresh Golla1
1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
JCI insight
|January 4, 2024
概括
巨细胞上高级糖化最终产品 (RAGE) 的受体在非酒精性脂肪肝炎 (NASH) 中促进肝炎. 准巨细胞中的RAGE信号可能为NASH提供一种新的治疗策略.
科学领域:
- 免疫学 免疫学 免疫学
- 肝病学 肝病学是一种肝病学.
- 分子生物学分子生物学
背景情况:
- 在非酒精性脂肪肝炎 (NASH) 中,肝脏内巨是多种多样的,包括由单细胞衍生的炎症性巨.
- 先进的糖化最终产品 (RAGE) 的受体存在于巨细胞上,并在NASH中被损伤相关分子模式 (DAMPs) 激活.
- 巨细胞RAGE信号传递在NASH病变发生过程中的具体作用尚不清楚.
研究的目的:
- 为了研究RAGE表达性巨细胞是前炎性,并有助于NASH肝炎的假设.
- 探索RAGE作为NASH的潜在治疗点.
主要方法:
- 在人类NASH肝脏活检中的RAGE表达的分析以及由高脂肪,高果糖和高胆固醇 (FFC) 饮食诱导的NASH的小鼠模型.
- 使用TTP488的RAGE的药理抑制和RAGE在髓状细胞 (RAGE-MKO小鼠) 中的基因切除.
- 评估肝损伤,巨细胞透,转录和T细胞激活.
主要成果:
- 在NASH患者中,RAGE表达升高,特别是在FFC诱导的NASH模型中招募的巨细胞上.
- RAGE抑制 (TTP488) 和骨髓特异性RAGE淘汰 (RAGE-MKO) 减轻了肝损伤和减少了RAGE+巨细胞的积累.
- FFC饮食上调了巨细胞和T细胞激活通路,这些通路被TTP488抑制,并在RAGE-MKO小鼠中减少.
- 来自RAGE-MKO小鼠的巨细胞分泌体显示其激活CD8+T细胞的能力降低.
结论:
- 在招募的巨细胞中,RAGE信号与促进NASH肝炎的肝炎有关.
- RAGE 是一种新且潜在的向性中介剂,可以在NASH中促进炎症性巨细胞活动.
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