环境与职业医学2026，Vol.43Issue(6)：717-729,13.DOI:10.11836/JEOM25496
二氧化硅通过Raf/ERK-SP1信号轴调控巨噬细胞CCL22分泌及其对肺上皮细胞纤维化的影响
Silicon dioxide regulates macrophage CCL22 secretion via Raf/ERK-SP1 signaling axis and its ef-fect on pulmonary epithelial cell fibrosis
摘要
Abstract
[Background]Silicosis is a fatal form of pulmonary fibrosis caused by the inhalation of silica dust.Although the underlying pathogenesis remains unclear,and the macrophage-mediated immune response plays a central role in its development. [Objective]To investigate the expression,functional role,and upstream regulatory mechanism of C-C motif chemokine ligand 22(CCL22)in silica-induced pulmonary fibrosis. [Methods]Through bioinformatics analysis,we identified CCL22 as a potential key factor in pulmonary fibrosis.We established in vitro models by stimulating human monocytic leukemia cells(THP-1)and peripheral blood mononuclear cell-derived macrophages(PBMC-m)with crystalline silica(CS).The regulation of CCL22 expression by CS was validated using quantitative real-time polymerase chain reaction(qRT-PCR)and enzyme-linked immunosorbent assay(ELISA).Subsequently,a conditioned co-culture system comprising macrophages and lung epithelial cells(BEAS-2B)was developed to evaluate the effects of CCL22 on lung epithelial cell function.Furthermore,the molecular mechanisms underlying CS-induced CCL22 secretion by macrophages were investigated using bioinformatics analysis,Western blot,specific inhibitors,qRT-PCR,and ELISA. [Results]Bioinformatics analysis identified CCL22 as a key upregulated molecule in pulmonary fibrosis.In vitro experiments confirmed that CS treatment significantly enhanced CCL22 mRNA transcription and protein secretion in THP-1 and PBMC-m cells(P<0.0001).In the co-culture system,supernatant from CS-stimulated macrophages with stable CCL22 knockdown significantly inhibited the scratch-healing ability and fibrotic process of BEAS-2B cells,and reversed the epithelial-mesenchymal transition(EMT)phenotype compared to the control group.Mechanism studies found that,compared to other transcription factors such as signal transducer and activator of transcription 3(STAT3)and nuclear factor-κB(NF-κB),the inhibition of of specific protein 1(SP1)most significantly attenuated the CS-induced upregulation of CCL22.Furthermore,pathway inhibition experiments demonstrated that inhibiting extracellular signal-regulated kinase(ERK)reduced both CCL22 expression and p-SP1.Conversely,SP1 intervention did not affect ERK activation. [Conclusion]CS promotes CCL22 secretion by macrophages through the Raf/ERK-Sp1 signaling pathway,thereby driving fibrotic changes in pulmonary epithelial cells.关键词
二氧化硅粉尘/巨噬细胞/C-C基序趋化因子配体22/上皮-间充质转化/肺纤维化Key words
silica dust/macrophage/CCL22/epithelial-mesenchymal transition/pulmonary fibrosis分类
医药卫生引用本文复制引用
安敬芝,吴静,帕热依扎·加伦别克,周家伟,郭健强,成安琪,柏英,胡东..二氧化硅通过Raf/ERK-SP1信号轴调控巨噬细胞CCL22分泌及其对肺上皮细胞纤维化的影响[J].环境与职业医学,2026,43(6):717-729,13.基金项目
安徽省临床医学研究转化专项项目(202427b10020117,202427b10020102) （202427b10020117,202427b10020102）
国家自然科学基金项目(42042055,82404727) （42042055,82404727）
安徽省科技创新攻坚计划项目(202423l10050053) （202423l10050053）
工业粉尘深度净化与职业健康安全安徽省高校重点实验室开放基金项目(AYZJSGXLK202401002,AYZJSGXLK202402002) This study was funded. （AYZJSGXLK202401002,AYZJSGXLK202402002）
