Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning, PR China.
Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, PR China.
Nat Commun. 2024 Nov 12;15(1):9770. doi: 10.1038/s41467-024-54174-5.
Crystalline silica (CS) particle exposure leads to silicosis which is characterized as progressive fibrosis. Fibroblasts are vital effector cells in fibrogenesis. Emerging studies have identified immune sentinel roles for fibroblasts in chronic disease, while their immune-modulatory roles in silicosis remain unclear. Herein, we show that group 2 innate lymphoid cell (ILC2) conversion to ILC1s is closely involved in silicosis progression, which is mediated by activated fibroblasts via interleukin (IL)-18. Mechanistically, Notch3 signaling in mechanics-activated fibroblasts modulates IL-18 production via caspase 1 activity. The mouse-specific Notch3 knockout in fibroblasts retards pulmonary fibrosis progression that is linked to attenuated ILC conversion. Our results indicate that activated fibroblasts in silicotic lungs are regulators of ILC2-ILC1 conversion, associated with silicosis progression via the Notch3-IL-18 signaling axis. This finding broadens our understanding of immune-modulatory mechanisms in silicosis, and indicates potential therapeutic targets for lung fibrotic diseases.
结晶二氧化硅（CS）颗粒暴露会导致矽肺，其特征为进行性纤维化。成纤维细胞是纤维化发生的重要效应细胞。新兴研究已经确定了成纤维细胞在慢性疾病中的免疫哨兵作用，而它们在矽肺中的免疫调节作用尚不清楚。在此，我们表明，2 组先天淋巴样细胞（ILC2）向 ILC1 的转化与矽肺进展密切相关，这是由激活的成纤维细胞通过白细胞介素（IL）-18 介导的。在机制上，力学激活的成纤维细胞中的 Notch3 信号通过半胱天冬酶 1 活性调节 IL-18 的产生。成纤维细胞中特异性的 Notch3 敲除会减缓肺纤维化的进展，这与 ILC 转化的减弱有关。我们的结果表明，矽肺肺中的激活成纤维细胞是 ILC2-ILC1 转化的调节剂，通过 Notch3-IL-18 信号轴与矽肺进展相关。这一发现拓宽了我们对矽肺中免疫调节机制的理解，并表明肺纤维化疾病的潜在治疗靶点。
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