Silicon dioxide regulates macrophage CCL22 secretion via Raf/ERK-SP1 signaling axis and its effect on pulmonary epithelial cell fibrosis

Jingzhi AN; Jing WU; Jialunbieke PAREYIZA; Jiawei ZHOU; Jianqiang GUO; Anqi CHENG; Ying BAI; Dong HU

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Silicon dioxide regulates macrophage CCL22 secretion via Raf/ERK-SP1 signaling axis and its effect on pulmonary epithelial cell fibrosis

VernacularTitle: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
Author: Jingzhi AN ¹ ; Jing WU ² ; Jialunbieke PAREYIZA ¹ ; Jiawei ZHOU ¹ ; Jianqiang GUO ¹ ; Anqi CHENG ¹ ; Ying BAI ¹ ; Dong HU ³
Author Information

1. School of Medicine.
2. Bozhou Clinical Medical College of Anhui University of Science and Technology (Bozhou People's Hospital), Bozhou, Anhui 236800, China.
3. The First Affiliated Hospital of Anhui University of Science and Technology, Huainan, Anhui 232001, China.
Publication Type:Selectedarticle
Keywords: silica dust; macrophage; CCL22; epithelial-mesenchymal transition; pulmonary fibrosis
From: Journal of Environmental and Occupational Medicine 2026;43(6):717-729
CountryChina
Language:Chinese
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.