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cGAS表达在与全身性硬化症相关的间歇性肺病中增强,并刺激炎症性肌纤维细胞激活

Sheeline Yu¹, Buqu Hu¹, Ying Sun¹

¹Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine.

The European respiratory journal

|May 15, 2025

概括

循环GMP-AMP合成酶 (cGAS) 信号驱动系统性硬化症相关间歇性肺部疾病 (SSc-ILD) 的炎症和纤维化. 抑制cGAS为SSc-ILD患者提供了潜在的新疗法.

科学领域:

免疫学免疫学免疫学
肺部病理学肺部病理学
类风湿病学类风湿病学

背景情况:

系统性硬化症相关的间歇性肺病 (SSc-ILD) 涉及炎症性肌纤维细胞,纤维刺激和免疫失调.
目前尚不清楚细胞质DNA传感器循环GMP-AMP合成酶 (cGAS) 在SSc-ILD病原发生中的作用.

研究的目的:

在SSc-ILD.中调查cGAS表达,活性和治疗潜力.
通过使用各种模型,探索cGAS在SSc-ILD病原体中的参与.

主要方法:

在SSc-ILD肺组织,支气管支气管洗 (BAL) 和纤维细胞体中评估了cGAS,细胞因子和1型干扰素表达.
使用单细胞RNA测序数据评估cGAS激活,并测量了响应TGFβ1或机械刺激的细胞因子/干扰素产生.
在培养细胞,精密切割肺切片 (PCLS) 和白素诱导的肺纤维化小鼠模型中测试了cGAS抑制.

主要成果:

SSc-ILD肺组织和BAL显示了cGAS,细胞因子和1型干扰素的丰富.
cGAS通路在SSc-ILD纤维细胞中具有构成性活性,在正常肺纤维细胞中可通过TGFβ1或机械应力诱导.
抑制cGAS减少了细胞因子,1型干扰素和αSMA的体外和体内产生,这与白胺模型的发现相一致.

结论:

cGAS信号传递有助于SSc-ILD中炎症性肌纤维细胞表型的发展.
针对cGAS或其下游途径,为SSc-ILD提供了一个有前途的新疗法策略.

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