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MMP7 shedding of syndecan-1 facilitates re-epithelialization by affecting alpha(2)beta(1) integrin activation.

Chen P, Abacherli LE, Nadler ST, Wang Y, Li Q, Parks WC - PLoS ONE (2009)

Bottom Line: Because inflammation and repair are related events, we evaluated the role of syndecan-1 shedding in lung re-epithelialization.Additionally, we found that syndecan-1 augmented cell adhesion to collagen by controlling the affinity state of the alpha(2)beta(1) integrin.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, USA. petechen@u.washington.edu

ABSTRACT

Background: 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 re-epithelialization.

Methodology/principal finding: Epithelial 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 alpha(2)beta(1) integrin.

Conclusion/significance: MMP7 shedding of syndecan-1 facilitates wound closure by causing the alpha(2)beta(1) 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.

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Wounded Sdc1−/− lung epithelium is unaffected byα2β1 integrin inhibition.Wild-type and Sdc1−/− ALI cultures were injured in the presence of a control (hamster isotype IgG2; 10 µg/ml), α2 integrin subunit inhibiting antibody (clone Ha1/29; 10 µg/ml) or α2β1 integrin inhibiting peptide (5 mM). The percent wound closure was determined 24 h after injury. *p<0.05 by 2-way ANOVA and Bonferroni analysis. n = 4; Original magnification×100.
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pone-0006565-g005: Wounded Sdc1−/− lung epithelium is unaffected byα2β1 integrin inhibition.Wild-type and Sdc1−/− ALI cultures were injured in the presence of a control (hamster isotype IgG2; 10 µg/ml), α2 integrin subunit inhibiting antibody (clone Ha1/29; 10 µg/ml) or α2β1 integrin inhibiting peptide (5 mM). The percent wound closure was determined 24 h after injury. *p<0.05 by 2-way ANOVA and Bonferroni analysis. n = 4; Original magnification×100.

Mentions: To test these ideas, we first established that blocking the α2β1 integrin enhances wound repair in ALI airway epithelial cultures. Wounded WT ALI cultures had enhanced wound closure in the presence of either an α2 subunit inhibiting antibody or an α2β1 inhibiting peptide (Figure 5 and 6). In contrast, Sdc1−/− ALI cultures had no additional augmentation of wound closure suggesting the α2β1 integrin contributed minimally to cell migration in the absence of syndecan-1 (Figure 5). However, and consistent with our hypothesis, the α2 subunit and α2β1 integrin inhibitors both increased the wound closure rate of injured Mmp7−/− ALI cultures (Figure 6). These data support our idea that in the presence of syndecan-1, the higher affinity state of the α2β1 integrin restrains migration of the repairing airway epithelium.


MMP7 shedding of syndecan-1 facilitates re-epithelialization by affecting alpha(2)beta(1) integrin activation.

Chen P, Abacherli LE, Nadler ST, Wang Y, Li Q, Parks WC - PLoS ONE (2009)

Wounded Sdc1−/− lung epithelium is unaffected byα2β1 integrin inhibition.Wild-type and Sdc1−/− ALI cultures were injured in the presence of a control (hamster isotype IgG2; 10 µg/ml), α2 integrin subunit inhibiting antibody (clone Ha1/29; 10 µg/ml) or α2β1 integrin inhibiting peptide (5 mM). The percent wound closure was determined 24 h after injury. *p<0.05 by 2-way ANOVA and Bonferroni analysis. n = 4; Original magnification×100.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2719060&req=5

pone-0006565-g005: Wounded Sdc1−/− lung epithelium is unaffected byα2β1 integrin inhibition.Wild-type and Sdc1−/− ALI cultures were injured in the presence of a control (hamster isotype IgG2; 10 µg/ml), α2 integrin subunit inhibiting antibody (clone Ha1/29; 10 µg/ml) or α2β1 integrin inhibiting peptide (5 mM). The percent wound closure was determined 24 h after injury. *p<0.05 by 2-way ANOVA and Bonferroni analysis. n = 4; Original magnification×100.
Mentions: To test these ideas, we first established that blocking the α2β1 integrin enhances wound repair in ALI airway epithelial cultures. Wounded WT ALI cultures had enhanced wound closure in the presence of either an α2 subunit inhibiting antibody or an α2β1 inhibiting peptide (Figure 5 and 6). In contrast, Sdc1−/− ALI cultures had no additional augmentation of wound closure suggesting the α2β1 integrin contributed minimally to cell migration in the absence of syndecan-1 (Figure 5). However, and consistent with our hypothesis, the α2 subunit and α2β1 integrin inhibitors both increased the wound closure rate of injured Mmp7−/− ALI cultures (Figure 6). These data support our idea that in the presence of syndecan-1, the higher affinity state of the α2β1 integrin restrains migration of the repairing airway epithelium.

Bottom Line: Because inflammation and repair are related events, we evaluated the role of syndecan-1 shedding in lung re-epithelialization.Additionally, we found that syndecan-1 augmented cell adhesion to collagen by controlling the affinity state of the alpha(2)beta(1) integrin.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, USA. petechen@u.washington.edu

ABSTRACT

Background: 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 re-epithelialization.

Methodology/principal finding: Epithelial 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 alpha(2)beta(1) integrin.

Conclusion/significance: MMP7 shedding of syndecan-1 facilitates wound closure by causing the alpha(2)beta(1) 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.

Show MeSH
Related in: MedlinePlus