Aberrant peribiliary gland niche exacerbates fibrosis in primary sclerosing cholangitis and a potential therapeutic strategy

Primary sclerosing cholangitis (PSC) is a rare but progressive and fatal autoimmune disease without clear pathogenesis and effective therapies. Peribiliary macrophage recruitment and peribiliary gland (PBG) proliferation and expansion have been associated with various cholangiopathies. This study aimed to evaluate the involvement of the PBG niche and macrophages in PSC progression, potential treatment strategies, and the underlying mechanism in acute and chronic experimental PSC. First, the upregulation of chemokines and fibrosis in PSC patients was confirmed via RNA-seq analysis. In vivo data illustrated that inflammation and fibrosis are the main characteristics, and recession of these can effectively interfere with PSC. Histopathological staining and RT-PCR revealed that more significant ductular reaction (DR) and PBG proliferation in the chronic PSC model, in which fibrosis mainly accumulated in the peribiliary area. In vitro, a transwell migration experiment showed that MCP-1 secreted by cholangiocytes in PBG niche, which recruited monocyte-derived macrophages (MoMFs) to the peribiliary area and promoted inflammation and fibrosis. Then, the luciferase assay and EMSA showed that POU6F1 could activate MCP-1 transcription. Furthermore, 18β-Glycyrrhetinic acid (GA) reduced macrophages and fibrosis accumulated in the peribiliary, space and reduced PBG proliferation to benefit acute and chronic PSC models. Collectively, our results indicated that POU6F1 transcriptionally activates MCP-1, promoting the recruitment and infiltration of MoMFs and fibrosis into the PBG niche in PSC mouse models, and GA effectively suppressed the above phenotypes. These findings provide potential targets and a theoretical basis for the clinical treatment of PSC. In the PSC models, the PBGs recruited macrophages through a POU6F1-mediated increase in MCP-1 transcription. The accumulation of macrophages resulted in inflammation, ductular reaction, and fibrosis, which could be alleviated by GA administration. [Display omitted] •Transcriptomic reanalysis in patients and experimental models suggested the disordered immune cells, abnormal proliferation, and increased fibrosis in primary sclerosing cholangitis.•MCP-1 originated from cholangiocyte, recruit and chemotaxis macrophages to the peribiliary area. POU6F1 transcriptional activated MCP-1, to promote PBGs proliferation and expansion.•18β-glycyrrhetinic acid (GA) holds therapeutic potential for the treatment of acute and chronic PSC