Cholangiopathies encompass chronic liver diseases in which damage to cholangiocytes—the epithelial cells lining the bile ducts—triggers both an inflammatory and a fibrotic response. The vitamin D nuclear receptor (VDR), strongly expressed in these cells, exerts immunoregulatory functions there. Previous work has shown that in patients with liver disease, certain variants of the VDR gene lead to low hepatic expression of the receptor, associated with more severe inflammation and fibrosis. Against this backdrop, the authors sought to clarify the protective role of VDR and that of other vitamin D signaling pathways in chronic cholangiopathy.
To this end, the Vdr gene was knocked out in mice already lacking Abcb4, a widely used animal model of chronic cholangiopathy. The impact of vitamin D signaling was assessed in vivo as well as in cholangiocytes, both primary cells and cell lines. The main features of the disease—cholestasis, ductular reaction, and fibrosis—were found to be aggravated in the doubly knocked-out Vdr;Abcb4 mice compared with mice deficient in Abcb4 alone, with this worsening accompanied by overexpression of pro-inflammatory factors. The pro-inflammatory phenotype of cholangiocytes was likewise exacerbated following VDR silencing in vitro.
Administration to the doubly knocked-out mice of a vitamin D analog, calcipotriol, or of vitamin D reduced the expression of pro-inflammatory factors and the severity of the cholangiopathy. Prolonged vitamin D supplementation notably attenuated the liver injury assessed at six months. In vitro, in biliary epithelial cells in which VDR had been silenced, calcipotriol significantly decreased the inflammatory response to TNFα; this effect disappeared when protein disulfide-isomerase A3 (PDIA3), a membrane receptor for vitamin D, was concomitantly silenced. The authors further observed overexpression of PDIA3 in the liver and cholangiocytes of VDR-deficient mice, as well as its presence at the plasma membrane of cholangiocytes in human liver sections.
This work establishes an anti-inflammatory role for VDR signaling in cholangiocytes and cholangiopathy, and highlights anti-inflammatory effects of vitamin D and its analog mediated by PDIA3, particularly in a context of defective VDR signaling. The authors suggest that patients' VDR status may be as decisive as circulating vitamin D levels, and that PDIA3 represents a potential therapeutic target in cholangiopathies. They nonetheless emphasize the current lack of specific ligands for this receptor, whose development remains necessary to further explore its involvement.