MCP-1 downregulates MMP-9 export via vesicular redistribution to lysosomes in rat portal fibroblasts.

Dashawn A Hickman,Brian Storrie,Jonathan A Dranoff,Gaurav Syal,Michel Fausther,Jessica R Goree,Elise G Lavoie

doi:10.14814/phy2.12153

Dashawn A Hickman, Brian Storrie + Show 5 more

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https://doi.org/10.14814/phy2.12153

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Abstract

Portal fibroblasts (PF) are one of the two primary cell types contributing to the myofibroblast population of the liver and are thus essential to the pathogenesis of liver fibrosis. Monocyte chemoattractant protein‐1 (MCP‐1) is a known profibrogenic chemokine that may be of particular importance in biliary fibrosis. We examined the effect of MCP‐1 on release of matrix metalloproteinase‐9 (MMP‐9) by rat PF. We found that MCP‐1 blocks PF release of MMP‐9 in a posttranslational fashion. We employed an optical and electron microscopic approach to determine the mechanism of this downregulation. Our data demonstrated that, in the presence of MCP‐1, MMP‐9‐containing vesicles were shunted to a lysosome‐like compartment. This is the first report of a secretory protein to be so regulated in fibrogenic cells.

Highlights

Cirrhosis is the most important cause of liver failure and a major cause of mortality worldwide (Ratib et al 2014)
Expression of matrix metalloproteinase-9 (MMP-9)-CFP or CFP alone was accomplished by transient transfection of Day 5 Portal fibroblasts (PF) using TransMessenger Transfection Reagent (Qiagen), and cells were visualized at 48 h, so that cells were at day 7 during observation
Live day 7 PF cells transfected with matrix metalloproteinases (MMPs)-9-CFP or CFP were incubated with 50 nmol/L Lysotracker Red (Invitrogen) for 30 min at 37°C

Summary

Introduction

Cirrhosis is the most important cause of liver failure and a major cause of mortality worldwide (Ratib et al 2014). It has long been clear that there are two distinct varieties of cirrhosis: biliary and nonbiliary. Nonbiliary cirrhosis is caused by such conditions as chronic viral hepatitis, alcoholic liver disease, and nonalcoholic fatty liver disease and accounts for the majority of adult cirrhosis. While biliary cirrhosis accounts for only one in five cases of liver failure in adults, it is the predominant cause of liver failure in children (Alpini et al 2002). Biliary cirrhosis has long been known to be distinct in several ways: it progresses rapidly and is associated with more severe presinusoidal portal hypertension

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