Inflammatory factor CCL2 enhances the interaction between monocyte-macrophage cells and liver parenchymal cells to promote liver inflammation and fibrosis in biliary atresia

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: = 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.