Senescent pulmonary epithelial cells-derived S100A10 drives epithelial-fibroblast crosstalk through inhibiting vimentin ubiquitination in pulmonary fibrosis

Pulmonary fibrosis is a chronic, lethal, and ageing-associated interstitial lung disease of unknown aetiology, involves pulmonary epithelial cell senescence and fibroblast activation. However, the underlying mechanism remains elusive. This study aims to investigate the role and potential mechanism of aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis. The model of pulmonary fibrosis was established by intratracheal injection with bleomycin (BLM). The multiple co-culture systems were designed. Differentially expressed proteins in the supernatant of senescent epithelial cells were identified via Astral-DIA proteomics. The role of S100A10 in fibrosis was investigated through its knockdown and overexpression. BLM exposure induced fibroblast activation and pulmonary epithelial cell senescence. By establishing multiple coculture systems, conditioned medium from BLM-induced senescent mouse lung epithelial (MLE)-12 cells was used to activate L929 (normal murine fibroblasts) cells. Astral-DIA proteomics assay indicated that S100A10 was evidently increased in BLM-induced senescent pulmonary epithelial cells. Moreover, pulmonary epithelial cell-derived S100A10 induced fibroblast activation. In contrast, pulmonary epithelial cell-specific S100A10 knockdown alleviated BLM-evoked fibroblast activation and pulmonary fibrosis in mice. Mechanistically, senescent pulmonary epithelial cell-derived S100A10 activated fibroblasts by increasing the interaction between S100A10 and vimentin and then inhibited vimentin ubiquitination and degradation in fibroblasts. Our study highlights the critical role of senescent pulmonary epithelial cells by secreting S100A10, which induces pulmonary fibrosis by facilitating epithelial‒fibroblast crosstalk via vimentin ubiquitination and degradation. Therefore, S100A10 may be a potential therapeutic target for pulmonary fibrosis.