Mechanics-activated fibroblasts promote pulmonary group 2 innate lymphoid cell plasticity propelling silicosis progression

Yangyang He, Fan Yang, Lin Yang, Haoyang Yuan, Yichuan You, Yinghui Chen, Xiulin Wu, Hui Min, Jie Chen () and Chao Li ()
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Yangyang He: Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education
Fan Yang: Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education
Lin Yang: Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education
Haoyang Yuan: Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education
Yichuan You: Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education
Yinghui Chen: Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education
Xiulin Wu: Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education
Hui Min: China Medical University
Jie Chen: Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education
Chao Li: Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54174-5

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