MMP7 Shedding of Syndecan-1 Facilitates Re-Epithelialization by Affecting α2β1 Integrin Activation

Peter Chen,Laura E Abacherli,Qinglang Li,Ying Wang,Samuel T Nadler,William C Parks,Neeraj Vij

doi:10.1371/journal.pone.0006565

Abstract

BackgroundLung injury promotes the expression of matrix metalloproteinase-7 (MMP7, matrilysin), which is required for neutrophil recruitment and re-epithelialization. MMP7 governs the lung inflammatory response through the shedding of syndecan-1. Because inflammation and repair are related events, we evaluated the role of syndecan-1 shedding in lung re-epithelialization.Methodology/Principal FindingEpithelial injury induced syndecan-1 shedding from wild-type epithelium but not from Mmp7−/− mice in vitro and in vivo. Moreover, cell migration and wound closure was enhanced by MMP7 shedding of syndecan-1. Additionally, we found that syndecan-1 augmented cell adhesion to collagen by controlling the affinity state of the α2β1 integrin.Conclusion/SignificanceMMP7 shedding of syndecan-1 facilitates wound closure by causing the α2β1 integrin to assume a less active conformation thereby removing restrictions to migration. MMP7 acts in the lungs to regulate inflammation and repair, and our data now show that both these functions are controlled through the shedding of syndecan-1.

Highlights

Being contiguous with the environment, mucosal surfaces are constantly exposed to toxic and pathogenic insults [1,2]
We proposed that Ecadherin shedding could promote repair by reorganizing cell-cell contacts, newer studies indicate that MMP7 shedding of Ecadherin functions in adaptive immune responses later in the response to injury (McGuire et al, unpublished observations)
MMP7 is required for cell migration Air-liquid interface (ALI) cultures of airway epithelial cells differentiate into a complete mucociliary epithelium and act phenotypically similar to the in vivo epithelium providing a relevant organotypic culture system to study the airway mucosal epithelium [6]

Summary

Introduction

Being contiguous with the environment, mucosal surfaces are constantly exposed to toxic and pathogenic insults [1,2]. As a first line of defense, mucosal epithelia have evolved to quickly respond to various forms of injury by coordinating the inflammatory response while repairing wounded tissue. MMP7 (matrilysin), a member of the matrix metalloproteinase (MMP) family, is expressed by all mucosal surfaces and is quickly upregulated in response to epithelial injury [3,4,5,6,7,8,9,10,11]. Like other mucosal surfaces, injured lungs quickly initiate a preprogrammed response to recruit inflammatory cells and repair the damaged tissue. The roles of MMP7 in regulating repair and inflammation are prominent in the lungs. Lung injury promotes the expression of matrix metalloproteinase-7 (MMP7, matrilysin), which is required for neutrophil recruitment and re-epithelialization. MMP7 governs the lung inflammatory response through the shedding of syndecan-1. Because inflammation and repair are related events, we evaluated the role of syndecan-1 shedding in lung reepithelialization

Methods

Results

Conclusion