Selective Targeting of α4β7/MAdCAM-1 Axis Suppresses Fibrosis Progression by Reducing Proinflammatory T Cell Recruitment to the Liver

作者：Biki Gupta, Ravi Rai, Pabitra Bikash Pal, Daniel Rossmiller, Sudrishti Chaudhary, Anna Chiaro, Shannon Seaman, Aatur D. Singhi, Silvia Liu, Satdarshan P. Monga, Smita S. Iyer, Reben Raeman · 发表于：Cells · 年份：2024 · DOI：10.3390/cells13090756 · 被引用次数：12 · 研究领域：Liver physiology and pathology、Liver Diseases and Immunity、T-cell and B-cell Immunology

Integrin α4β7+ T cells perpetuate tissue injury in chronic inflammatory diseases, yet their role in hepatic fibrosis progression remains poorly understood. Here, we report increased accumulation of α4β7+ T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl4-induced liver fibrosis was associated with enrichment of intrahepatic α4β7+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α4β7 or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl4-treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of α4β7+ CD4 and CD8 T cells, suggesting that α4β7/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α4β7+ T cells promote hepatic fibrosis progression. Analysis of hepatic α4β7+ and α4β7- CD4 T cells revealed that α4β7+ CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that α4β7+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α4β7 or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.