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

Area of Science:

• Immunology
• Hepatology
• Molecular Biology

Background:

• Programmed death-ligand 1 (PD-L1) on hepatic stellate cells (HSCs) is crucial for HSC activation and immune suppression.
• HSC PD-L1's role in liver inflammation and fibrosis is not fully understood.

Purpose of the Study:

• To investigate the effect of targeting HSC PD-L1 on liver inflammation and fibrosis.
• To explore the molecular mechanisms by which PD-L1 on HSCs influences liver injury.

Main Methods:

• Generated HSC-specific PD-L1 knockout (PD-L1^HSCKO) mice.
• Administered carbon tetrachloride (CCl₄) to induce liver injury in PD-L1^HSCKO and wild-type (PD-L1^HSCWT) mice.
• Assessed liver fibrosis, HSC activation, inflammation, and performed multiomics analysis.

Main Results:

• PD-L1^HSCKO mice showed reduced collagen deposition and myofibroblast density compared to PD-L1^HSCWT mice.
• HSC-specific PD-L1 knockout led to increased lymphocyte infiltration but decreased myeloid cell infiltration.
• Targeting PD-L1 altered HSC transcriptomics and cytokine/chemokine secretion profiles, impacting HSC-immune cell interactions.

Conclusions:

• Targeting HSC PD-L1 suppresses liver fibrosis and modulates liver inflammation.
• Altering HSC PD-L1 impacts HSC transcriptome and immune cell dynamics.
• HSC PD-L1 represents a potential therapeutic target for liver fibrosis.