Blocking integrin α4β7-mediated CD4 T cell recruitment to the intestine and liver protects mice from western diet-induced non-alcoholic steatohepatitis.

Journal of Hepatology
Ravi P RaiReben Raeman

Abstract

The heterodimeric integrin receptor α4β7 regulates CD4 T cell recruitment to inflamed tissues, but its role in the pathogenesis of non-alcoholic steatohepatitis (NASH) is unknown. Herein, we examined the role of α4β7-mediated recruitment of CD4 T cells to the intestine and liver in NASH. Male littermate F11r+/+ (control) and junctional adhesion molecule A knockout F11r-/- mice were fed a normal diet or a western diet (WD) for 8 weeks. Liver and intestinal tissues were analyzed by histology, quantitative reverse transcription PCR (qRT-PCR), 16s rRNA sequencing and flow cytometry. Colonic mucosa-associated microbiota were analyzed using 16s rRNA sequencing. Liver biopsies from patients with NASH were analyzed by confocal imaging and qRT-PCR. WD-fed knockout mice developed NASH and had increased hepatic and intestinal α4β7+ CD4 T cells relative to control mice who developed mild hepatic steatosis. The increase in α4β7+ CD4 T cells was associated with markedly higher expression of the α4β7 ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the colonic mucosa and livers of WD-fed knockout mice. Elevated MAdCAM-1 expression correlated with increased mucosa-associated Proteobacteria in the WD-fed knockout mice. Antibiotic...Continue Reading

Citations

Dec 4, 2020·Cellular & Molecular Immunology·Hua WangYaron Rotman
May 4, 2021·Frontiers in Immunology·Rosa Martín-Mateos, Agustín Albillos
May 27, 2021·American Journal of Physiology. Gastrointestinal and Liver Physiology·Samar H Ibrahim
Sep 1, 2021·Seminars in Immunopathology·Franziska MuscateNicola Gagliani
Aug 19, 2021·American Journal of Physiology. Gastrointestinal and Liver Physiology·Kinga JaworskaMarcin Ufnal
Oct 12, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jonathon J GrahamBu'Hussain Hayee
Jan 14, 2022·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Pierluigi RamadoriMathias Heikenwalder

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