Splenic B Cells Accumulate and Adopt a Pro-Inflammatory Phenotype to Accelerate Fibrosis in a CCl4-Induced Liver Fibrosis Model.

The spleen plays a significant role in hepatic fibrosis progression. B cells are the main splenic lymphocytes, but their specific contributions and underlying mechanisms remain unclear. Hepatic fibrosis was induced in mice by intraperitoneal administration of carbon tetrachloride (CCl4). Splenectomy or sham operation was performed during the fibrotic process. Hepatic fibrosis severity and the proportion of splenic B cells were assessed. Splenic B cells isolated from fibrotic and control mice underwent mRNA sequencing. Protein expression of phosphorylated-p38 MAPK (p-p38 MAPK), total p38 MAPK, phosphorylated-NF-κB p65 (p-NF-κB p65), and total NF-κB p65 were determined by Western blotting using total protein extracted from the splenic B cells. Signal transduction pathways were investigated in isolated splenic B cells to elucidate mechanisms of phenotypic alteration. CCl4-induced hepatic fibrosis was associated with B-cell accumulation in both the liver and spleen. Compared with the splenectomized mice, sham-operated fibrotic mice exhibited a higher proportion of hepatic B cells and more severe liver fibrosis. Splenic B cells from fibrotic mice showed an expansion of the IL-6-producing subset and elevated expression of pro-inflammatory cytokines. Moreover, splenectomy reduced the proportion of B cells within the fibrotic liver. Splenic B cells from fibrotic mice displayed upregulated expression of p-p38 MAPK and p-NF-κB p65. In CCl4-induced hepatic fibrosis, splenic B cells accumulate and adopt a pro-inflammatory phenotype. This shift, mediated through activation of the p38 MAPK/NF-κB signaling pathway, promotes hepatic fibrosis progression. These findings identify splenic B cells as potential therapeutic targets for managing liver disease.