Work

Targeting Hepatic Stellate Cell PD-L1 Alters Liver Inflammation and Fibrosis in CCl4 Liver Injury Mouse Model

Year: 2025

Type: article

Abstract: Background & Aims Programmed death-ligand 1 (PD-L1) on hepatic stellate cells (HSCs) is required for HSC activation and suppressing T and B lymphocytes. We tested whether targeting HSC PD-L1 influenced liver inflammation and fibrosis in a carbon tetrachloride (CCl 4 ) injury mouse model. Methods HSC-specific PD-L1 knockout (PD-L1 HSCKO ) mice were created by crossing Cd274 floxed mice to Collagen1A1- Cre mice. CCl 4 was injected into PD-L1 HSCKO and PD-L1 HSCWT mice twice weekly for 6 weeks. Liver fibrosis was assessed by Trichrome and Picrosirius Red staining; HSC activation was determined by immunofluorescence and Western blot for HSC activation markers; liver inflammation was studied by multiplex immunofluorescence and cytokine profiling. Multiomics was leveraged to determine how targeting PD-L1 altered HSC producing collagens and cytokines/chemokines. Results Collagen deposition was reduced in CCl 4 -injured PD-L1 HSCKO livers compared with CCl 4 -injured PD-L1 HSCWT livers; myofibroblast density was lower in CCl 4 -injured PD-L1 HSCKO livers compared with CCl 4 -injured PD-L1 HSCWT livers. CCl 4 -injured PD-L1 HSCKO livers had higher lymphocyte densities (GranzymeB+, CD8a+, CD20+) but lower Kupffer and myeloid cell densities (F4/80+ and CD11b+) compared with CCl 4 -injured PD-L1 HSCWT livers. Serum aspartate aminotransferase and alanine aminotransferase, however, were similarly elevated by CCl 4 in both groups. Spatial and bulk-cell transcriptomics revealed a global transcriptomic change of HSCs induced by PD-L1 targeting. A targeted proteomics identified that HSC secretion of a group of cytokines/chemokines, including growth/differentiation factor 15, granulocyte-macrophage colony-stimulating factor, C-X-C motif and C-C motif chemokines, was altered upon PD-L1 targeting, highlighting the role of HSC PD-L1 in HSC/Kupffer and HSC/myeloid cell interactions during HSC activation and fibrosis development. Conclusions Targeting HSC PD-L1 altered HSC transcriptome and liver inflammation, and suppressed liver fibrosis, representing a potential therapeutic strategy for liver fibrosis.

Source: Cellular and Molecular Gastroenterology and Hepatology

DOI: 10.1016/j.jcmgh.2025.101587