Vitamin D3 attenuates hepatic inflammation in primary biliary cholangitis by inhibiting TLR4/NF-κB mediated M1 macrophage polarization.

Primary biliary cholangitis (PBC) is an autoimmune liver disease in which macrophages play a critical role in disease progression. Vitamin D3 (VitD3) exerts immunomodulatory effects and can regulate the phenotype and function of macrophages. However, the role of VitD3 in modulating macrophage polarization during PBC progression remains unclear. In this study, the relationship between VitD3 levels and macrophage polarization in PBC patients was evaluated by bioinformatics as well as clinical validation, and the underlying mechanisms were investigated using a mouse model of PBC and an in vitro cellular model. Bioinformatics analysis of vitamin D-related genes involved in PBC disease. The number of M1-type macrophages is increased in the liver of PBC patients. After calcitriol treatment, the serum 25(OH)D3 level of PBC patients was increased, liver injury was alleviated, and the number of M1 macrophages in the liver was decreased. In the liver of PBC mice, VitD3 treatment significantly reduced the infiltration of inflammatory cells, especially M1 macrophages, and reduced the release of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), thereby alleviating liver injury. In vitro and in vivo experiments showed that VitD3 inhibited the expression of TLR4/NF-κB signaling pathway-related proteins TLR4 and MyD88 and the phosphorylation of p65 and IκB. In conclusion, VitD3 may attenuate M1 macrophage polarization through the TLR4/NF-κB signaling pathway, thereby ameliorating the liver inflammatory injury in PBC. This study provides novel insights into the immunomodulatory effects of VitD3 in PBC and highlights its potential therapeutic implications.