TRAIL deletion in myeloid cells augments cholestatic liver injury

Ductular reactive (DR) cells exacerbate cholestatic liver injury and fibrosis. In this study we posited that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) emanating from recruited macrophages restrains DR cell expansion by apoptosis, thereby limiting cholestatic liver injury. Cholestatic liver injury was induced in Wild type (WT), Trailfl/fl and in myeloid-specific Trail deleted (TrailΔmye) C57BL/6 mice using the DDC diet. The DDC diet induced injury and hepatomegaly. However, parameters of liver injury, fibrosis, ductular reaction and inflammation were all increased in the TrailΔmye mice as compared to the WT and Trailfl/fl mice. To better resolve the gene expression profile of cholangiocytes that may promote the recruitment of myeloid cells into the periportal neighborhood, we performed spatial transcriptomics on FPPE liver tissue sections from WT and TrailΔmye mice that were fed the control or DDC diet using the NanoString GeoMx DSP platform (Cat. No. 121401103, GeoMx NGS RNA WTA Mm). FPPE mouse liver tissue sections from wild type (WT) mice and TrailΔmye mice fed on control (CON) or DDC diets were examined post-cholestatic liver injury using Nanostring GeoMx DSP platform to identify differential gene expression in cholangiocytes and macrophages in periportal and parenchymal regions.