The adhesion molecules β7 integrin and L-selectin contribute to cholestatic liver disease in male mice

Background & Aims: Primary sclerosing cholangitis (PSC) is a long-term progressive disease, often occurring in conjunction with inflammatory bowel disease (IBD). Dysregulated immune cell migration and gut microbiota alterations are implicated in disease progression. Livers of PSC patients show upregulation of the endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1). Here we examined the role of the leukocytic adhesion molecules (AM) β7 integrin and L-selectin, both binding partners of MAdCAM-1, in an experimental mouse model resembling aspects of human PSC. Methods: Wild type (WT), β7 integrin-deficient (β7 -/- ), L-selectin-deficient (L-sel -/- ), and L-selectin/β7 integrin double-deficient (L-sel -/- /β7 -/- ) male mice were compared in the model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholangiopathy. The extent of pathology was evaluated by serum parameters, histology, flow cytometry, and expression of inflammatory mediators. Fecal microbiota changes were assessed by 16S rRNA amplicon sequencing and intestinal permeability was measured by FITC-dextran assay. Results: AM-deficient mice were markedly protected from DDC-induced cholangiopathy. Hepatic immune cell populations of AM-deficient mice differed significantly from those of WT mice. Adoptively transferred β7 -/- CD8 + T cells caused significantly less liver damage than CD8 + WT T cells in DDC-treated β7 -/- mice. DDC-feeding caused substantial changes in fecal microbiota profiles, which differed between the mouse strains, and a strong increase in intestinal permeability that was significantly lower in β7 -/- than WT mice. Conclusions: β7 integrin and L-selectin contribute to DDC-induced cholangiopathy with β7 integrin-expressing CD8 + T cells playing a crucial role in promoting pathogenesis. In addition, AM-expressing immune cells may contribute to the inflammatory process by causing unfavorable gut microbiota shifts and destabilizing the gut barrier.