Author:
Krishnan Anuradha,Ozturk Nazli Begum,Cutshaw Kaiyel A.,Guicciardi Maria Eugenia,Kitagataya Takashi,Olson Kirsta E.,Pavelko Kevin D.,Sherman William,Wixom Alexander Q.,Jalan-Sakrikar Nidhi,Baez-Faria Michelle,Gutierrez Florencia,Gores Gregory J.
Abstract
AbstractDuctular reactive (DR) cells exacerbate cholestatic liver injury and fibrosis. Herein, we posit that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) emanates from recruited macrophages and restrains DR cell expansion, thereby limiting cholestatic liver injury. Wild type (WT), Trailfl/fl and myeloid-specific Trail deleted (TrailΔmye) C57BL/6 mice were exposed to DDC diet-induced cholestatic liver injury, which induced hepatomegaly and liver injury as compared to control diet-fed mice. However, parameters of liver injury, fibrosis, and inflammation were all increased in the TrailΔmye mice as compared to the WT and Trailfl/fl mice. High dimensional mass cytometry indicated that cholestasis resulted in increased hepatic recruitment of subsets of macrophages and neutrophils in the TrailΔmye mice. Spatial transcriptomics analysis revealed that the PanCK+ cholangiocytes from TrailΔmye mice had increased expression of the known myeloid attractants S100a8, Cxcl5, Cx3cl1, and Cxcl1. Additionally, in situ hybridization of Cxcl1, a potent neutrophil chemoattractant, demonstrated an increased expression in CK19+ cholangiocytes of TrailΔmye mice. Collectively, these data suggest that TRAIL from myeloid cells, particularly macrophages, restrains a subset of DR cells (i.e., Cxcl1 positive cells), limiting liver inflammation and fibrosis. Reprogramming macrophages to express TRAIL may be salutary in cholestasis.
Funder
PSC Partners Seeking a Cure
National Center for Advancing Translational Sciences
National Institute of Diabetes and Digestive and Kidney Diseases
NIDDK-funded Optical Microscopy Core of Mayo Clinic Center for Cell Signaling in Gastroenterology
Publisher
Springer Science and Business Media LLC