Paracrine signaling of ferroptotic airway epithelium in crystalline silica-induced pulmonary fibrosis augments local fibroblast activation through glycolysis reprogramming

• Published in: Ecotoxicology and environmental safety Vol. 271; p. 115994
• Main Authors: Li, Qianmin, Ling, Yi, Ma, Yu, Zhang, Tao, Yang, Youjing, Tao, Shasha
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.02.2024; Elsevier
• Subjects: AMPK-Glut1 axis; Crystalline silica; Ferroptosis; Glycolysis reprogramming; Paracrine signaling; BAY876; HK; Crystalline silica; BALF; 2-DG; Paracrine signaling; Ferroptosis; LW; DFO; Glycolysis reprogramming; ECM; 3-PO; ECAR; CS; LDH; FAO; BW; ROS; Ferr-1; AMPK-Glut1 axis
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2024.115994

Chronic exposure to crystalline silica (CS) contributes to pulmonary fibrosis. Airway epithelium dysfunction and fibroblast activation have both been recognized as pivotal players, alongside disturbances in ferroptosis and glycolysis reprogramming. However, the mechanisms involved remain unclear. In this study, we investigated the crosstalk between airway epithelium and fibroblast in the context of CS-induced pulmonary fibrosis. CS was employed in vivo and the in vitro co-culture system of airway epithelium and fibroblast. Spatial transcriptome analysis of CS-induced fibrotic lung tissue was conducted as well. Results showed that epithelium ferroptosis caused by CS enhanced TGFβ1-induced fibroblast activation through paracrine signaling. tPA was further identified to be the central mediator that bridges epithelium ferroptosis and fibroblast activation. And increased fibroblast glycolysis reprogramming was evidenced to promote fibroblast activation. By inhibition of epithelium ferroptosis or silencing tPA of airway epithelium, fibroblast AMPK phosphorylation was inhibited. Moreover, we revealed that tPA secreted by ferroptotic epithelium transmits paracrine signals to fibroblasts by governing glycolysis via p-AMPK/AMPK mediated Glut1 accumulation. Collectively, our study demonstrated the regulation of airway epithelium ferroptosis on fibroblast activation in CS-induced pulmonary fibrosis, which would shed light on the complex cellular crosstalk within pulmonary fibrosis and identify potential therapeutic targets. •CS exposure caused epithelium ferroptosis, enhancing TGFβ1-induced fibroblast activation through paracrine signaling.•tPA is vital for the crosstalk between epithelium ferroptosis and fibroblast activation.•The upregulated glycolysis of fibroblast is critical for its activation in CS-caused pulmonary fibrosis.•tPA secreted from ferroptotic epithelium orchestrates the glycolytic reprogramming of fibroblast through AMPK-Glut1 axis.