Mechanics-activated Fibroblasts orchestrating the plasticity of group 2 innate lymphoid cells propel the progression of silicosis

Abstract

Abstract Exposure to crystalline silica particle leads to silicosis characterized as progressive fibrosis. Fibroblasts are described as vital effector cells in fibrogenesis. Emerging studies identified immune sentinel role of fibroblasts in chronic disease, while their immune-modulatory role in silicosis remained elusive. Herein, we confirmed that a conversion of ILC2 to ILC1 closely involved in silicosis was mediated by activated fibroblast via IL-18. Mechanistically, Notch3 signaling in mechanics-activated fibroblasts modulated IL-18 production. The mice specific knockout Notch3 in fibroblast exerted retardatory progression of pulmonary fibrosis that tightly linked to attenuated conversion of ILCs. Our results indicated that the activated-fibroblast in silicotic lung served as a regulator of ILC2-ILC1 conversion that associated with silicosis progression via Notch3-IL-18 axis. The findings broadened the cognitive boundaries of the immune regulation of silicosis, also provide potential therapeutic targets in treating lung fibrotic diseases.