A&R:核受体4A亚家族信号转导是系统性硬化症中CD1c+树突状细胞失调的关键疾病通路

2022-08-06 紫菀款冬 MedSci原创

确定系统性硬化症(SSc)中驱动传统树突状细胞(cDC)改变的关键疾病通路。

目的:确定系统性硬化症(SSc)中驱动传统树突状细胞(cDC)改变的关键疾病通路

方法:对12名健康献血者和48名具有所有主要疾病亚型的SSc患者的外周血CD1c+cDCs(cDC2s)进行转录组学分析。进行差异表达分析,比较不同SSc亚型和健康供体,以发现SSc中失调的基因。为了确定生物学相关通路,使用加权基因相关网络分析构建了基因共表达网络。使用芯片测序和体外功能测定验证了关键转录调节因子的作用。

结果:在CDC中鉴定了17个共表达基因模块,这些基因模块与SSc亚型和关键临床特征(包括自身抗体、皮肤评分和间质性肺病的发生)相关。

在以严重纤维化为特征的弥漫性SSc亚型患者中,一组免疫调节基因显著下调。对该模块进行的转录调控网络分析预测NR4A(核受体4A)亚家族(NR4A1、NR4A2、NR4A3)基因是炎症的关键转录介质。事实上,芯片测序分析支持这些NR4A成员针对SSc cDC2s中的许多差异表达基因。

在基于培养的实验中纳入NR4A受体激动剂提供了功能证据,证明NR4As的失调影响cDC2s产生细胞因子并调节下游T细胞活化。

结论:NR4A1、NR4A2和NR4A3是SSc-cDCs中免疫抑制和纤维化相关通路的重要调节因子。NR4A家族可能是SSc中恢复cDC稳态的新的潜在靶点

文献来源:

https://onlinelibrary.wiley.com/doi/10.1002/art.42319

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    2022-12-01 ysjykql
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    2022-08-06 诗情的风

    很好的思路!

    0

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