Cellular and molecular gastroenterology and hepatology · 2025
Targeting Hepatic Stellate Cell PD-L1 Alters Liver Inflammation and Fibrosis in CCl4 Liver Injury Mouse Model.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Bai Bing, Bao Wenming, Wang Yuanguo, Shaha Aurpita, Kisseleva Tatiana, He Lianping, Sun Liankang, Jerez Sofia, Shah Vijay H, Wang Xianghu, Kang Ningling
Аннотация
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 (CCl4) injury mouse model.
METHODS: HSC-specific PD-L1 knockout (PD-L1HSCKO) mice were created by crossing Cd274 floxed mice to Collagen1A1-Cre mice. CCl4 was injected into PD-L1HSCKO and PD-L1HSCWT 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 CCl4-injured PD-L1HSCKO livers compared with CCl4-injured PD-L1HSCWT livers; myofibroblast density was lower in CCl4-injured PD-L1HSCKO livers compared with CCl4-injured PD-L1HSCWT livers. CCl4-injured PD-L1HSCKO livers had higher lymphocyte densities (GranzymeB+, CD8a+, CD20+) but lower Kupffer and myeloid cell densities (F4/80+ and CD11b+) compared with CCl4-injured PD-L1HSCWT livers. Serum aspartate aminotransferase and alanine aminotransferase, however, were similarly elevated by CCl4 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.
METHODS: HSC-specific PD-L1 knockout (PD-L1HSCKO) mice were created by crossing Cd274 floxed mice to Collagen1A1-Cre mice. CCl4 was injected into PD-L1HSCKO and PD-L1HSCWT 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 CCl4-injured PD-L1HSCKO livers compared with CCl4-injured PD-L1HSCWT livers; myofibroblast density was lower in CCl4-injured PD-L1HSCKO livers compared with CCl4-injured PD-L1HSCWT livers. CCl4-injured PD-L1HSCKO livers had higher lymphocyte densities (GranzymeB+, CD8a+, CD20+) but lower Kupffer and myeloid cell densities (F4/80+ and CD11b+) compared with CCl4-injured PD-L1HSCWT livers. Serum aspartate aminotransferase and alanine aminotransferase, however, were similarly elevated by CCl4 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.