Interleukin-11 drives fibroblast metabolic reprogramming in crystalline silica-induced lung fibrosis

• Published in: The Science of the total environment 2024-11, Vol.949, p.174976, Article 174976
• Main Authors: Xie, Yujia, Yang, Shiyu, Xu, Yiju, Gu, Pei, Zhang, Yingdie, You, Xiaojie, Yin, Haoyu, Shang, Bingxin, Yao, Yuxin, Li, Wei, Wang, Dongming, Zhou, Ting, Song, Yuanchao, Chen, Weihong, Ma, Jixuan
• Format: Article
• Language: English
• Subjects: Animals; Crystalline silica; Fibroblast metabolic reprogramming; Fibroblasts - drug effects; Glycolysis; Hypoxia inducible factor-1α; Interleukin-11; Interleukin-11 - metabolism; Lung fibrosis; Metabolic Reprogramming - drug effects; Mice; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - metabolism; Silicon Dioxide - toxicity; Silicosis - metabolism
• ISSN: 0048-9697; 1879-1026; 1879-1026
• DOI: 10.1016/j.scitotenv.2024.174976

Environmental exposure to crystalline silica (CS) particles is common and occurs during natural, industrial, and agricultural activities. Prolonged inhalation of CS particles can cause silicosis, a serious and incurable pulmonary fibrosis disease. However, the underlying mechanisms remain veiled. Herein, we aim to elucidate the novel mechanisms of interleukin-11 (IL-11) driving fibroblast metabolic reprogramming during the development of silicosis. We observed that CS exposure induced lung fibrosis in mice and activated fibroblasts, accompanied by increased IL-11 expression and metabolic reprogramming switched from mitochondrial respiration to glycolysis. Besides, we innovatively uncovered that elevated IL-11 promoted the glycolysis process, thereby facilitating the fibroblast-myofibroblast transition (FMT). Mechanistically, CS-stimulated IL-11 activated the extracellular signal-regulated kinase (ERK) pathway and the latter increased the expression of hypoxia inducible factor-1α (HIF-1α) via promoting the translation and delaying the degradation of the protein. HIF-1α further facilitated glycolysis, driving the FMT process and ultimately the formation of silicosis. Moreover, either silence or neutralization of IL-11 inhibited glycolysis augmentation and attenuated CS-induced lung myofibroblast generation and fibrosis. Overall, our findings elucidate the role of IL-11 in promoting fibroblast metabolic reprogramming through the ERK-HIF-1α axis during CS-induced lung fibrosis, providing novel insights into the molecular mechanisms and potential therapeutic targets of silicosis. [Display omitted] •Crystalline silica (CS) particles increase IL-11 expression in vivo and in vitro.•CS-induced IL-11 promotes the process of fibroblast-myofibroblast transition (FMT).•IL-11 leads to fibroblast metabolic reprogramming switched from OXPHOS to glycolysis.•IL-11 drives glycolysis via•the ERK-HIF-1α axis during silicosis and CS-induced FMT.•Targeting IL-11 attenuates CS-induced lung fibrosis and fibroblast activation.