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Integrin α 4 β 7 + 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 α 4 β 7 + T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl 4 -induced liver fibrosis was associated with enrichment of intrahepatic α 4 β 7 + CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α 4 β 7 or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl 4 -treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of α 4 β 7 + CD4 and CD8 T cells, suggesting that α 4 β 7 /MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α 4 β 7 + T cells promote hepatic fibrosis progression. Analysis of hepatic α 4 β 7 + and α 4 β 7 - CD4 T cells revealed that α 4 β 7 + CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that α 4 β 7 + T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α 4 β 7 or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.

Liver fibrosis arises from dysregulated wound healing due to persistent inflammatory hepatic injury. Periostin is a nonstructural extracellular matrix protein that promotes organ fibrosis in adults. Here, we sought to identify the molecular mechanisms in periostin-mediated hepatic fibrosis. Hepatic fibrosis in periostin -/- mice was attenuated as evidenced by significantly reduced collagen fibril density and liver stiffness compared with those in WT controls. A single dose of carbon tetrachloride caused similar acute liver injury in periostin -/- and WT littermates, and we did not detect significant differences in transaminases and major fibrosis-related hepatic gene expression between these two genotypes. Activated hepatic stellate cells (HSCs) are the major periostin-producing liver cell type. We found that in primary rat HSCs in vitro , periostin significantly increases the expression levels and activities of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) isoforms 1-3. Periostin also induced expression of intra- and extracellular collagen type 1 and fibronectin in HSCs. Interestingly, periostin stimulated phosphorylation of SMAD2/3, which was sustained despite short hairpin RNA-mediated knockdown of transforming growth factor β (TGFβ) receptor I and II, indicating that periostin-mediated SMAD2/3 phosphorylation is independent of TGFβ receptors. Moreover, periostin induced the phosphorylation of focal adhesion kinase (FAK) and AKT in HSCs. Notably, siRNA-mediated FAK knockdown failed to block periostin-induced SMAD2/3 phosphorylation. These results suggest that periostin promotes enhanced matrix stiffness in chronic liver disease by activating LOX and LOXL, independently of TGFβ receptors. Hence, targeting periostin may be of therapeutic benefit in combating hepatic fibrosis., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Alcohol consumption promotes loss of intestinal barrier function. However, mechanisms by which ethanol affects the tight junction (TJ), the cellular structure responsible for maintaining the gut epithelial barrier, are not well understood. Three classes of transmembrane proteins comprise TJs: occludin, claudins, and junctional adhesion molecules (JAMs). It has recently been postulated that JAM-A (F11R), the most abundant JAM expressed in intestinal epithelium, regulates "leak" pathway flux, a paracellular route for the nonselective permeation of large solutes. Since transluminal flux of many gut-derived antigens occurs through this pathway, we investigated the role of JAM-A in ethanol-induced disruption of the intestinal epithelial barrier. Using Caco-2 and SK-CO15 monolayers, we found that ethanol induced a dose- and time-dependent decrease in JAM-A protein expression to about 70% of baseline levels. Alcohol also reduced Ras-related protein 2 (Rap2) activity, and enhanced myosin light chain kinase (MLCK) activity, changes consistent with impaired JAM-A signaling. Stable overexpression and shRNA-mediated knockdown of JAM-A were employed to investigate the role of JAM-A in paracellular-mediated flux following alcohol exposure. The paracellular flux of 40-kDa fluorescein isothiocynate (FITC)-dextran following ethanol treatment was decreased by the overexpression of JAM-A; conversely, flux was enhanced by JAM-A knockdown. Thus, we conclude that ethanol-mediated control of JAM-A expression and function contributes to mechanisms by which this chemical induces intestinal epithelial leakiness., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)