Inflammatory factor CCL2 enhances the interaction between monocyte-macrophage cells and liver parenchymal cells to promote liver inflammation and fibrosis in biliary atresia
Abstract Background Liver fibrosis in biliary atresia (BA) progresses rapidly and has distinct characteristics; however, current studies have not identified effective prevention or treatment strategies to address this issue. Methods BA liver tissues with different degrees of liver fibrosis (n = 4),...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
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| Series: | BMC Pediatrics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12887-025-05984-z |
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| Summary: | Abstract Background Liver fibrosis in biliary atresia (BA) progresses rapidly and has distinct characteristics; however, current studies have not identified effective prevention or treatment strategies to address this issue. Methods BA liver tissues with different degrees of liver fibrosis (n = 4), liver tissues of choledochal cyst (n = 2), and liver tissues of the normal control (NC) group (n = 2) were selected. Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and Mendelian randomization (MR) were integrated for analysis. The clinical data of the sequenced samples, GSE176189 and GSE122340, were used to verify the results. Results The level of inflammation in the severe fibrosis group was significantly higher than that in the mild fibrosis group (adjusted P < 0.0001). The results of MR showed that CCL2 had a causal relationship with BA (odds ratio (OR) = 1.70, confidence interval (CI): 1.19 to 2.43, P = 0.004, P false discovery rate (FDR) = 0.117). The expression level of CCL2 in BA was significantly higher than that in NC (P < 0.001), and its expression level increased with the progression of fibrosis, mainly expressed in the central region of fibrosis. The pseudo-timing results of scRNA-seq showed that CXCL10 + intermediate monocytes may play a significant role in the early stages of fibrosis progression, while TREM2 + scar-associated macrophages may be more active in the later stages. OLR1 + M2 macrophages may represent a transitional state between the two cell types described above. The expression of CCL2 in these three cell subtypes was also higher than that in the others. CCL2 + monocyte-macrophage cells showed the strongest correlation with gamma-glutamyl transferase (R = 0.88, P = 0.0072). The interactions between CCL2 + monocyte-macrophage cells and hepatocytes, hepatic stellate cells, and bile duct epithelial cells were significantly upregulated in BA (P < 0.01). These interactions were more prominent in mild fibrosis than severe fibrosis (P < 0.01). Conclusions Severe liver fibrosis in BA is associated with a pronounced inflammatory response. CCL2 may be crucial in the occurrence and progression of liver fibrosis in BA. Targeting CCL2 + monocyte-macrophage cells by reducing their proportion or interaction with liver fibrosis-related cells may provide a potential treatment for liver fibrosis in BA. |
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| ISSN: | 1471-2431 |