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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 has attenuated repair with forced β1 integrin subunit activation.Wild-type and Sdc1−/− ALI cultures were injured in the presence of a control (rat isotype IgG, 1 µg/ml) or β1 integrin subunit activating (clone 9EG7, 1 µg/ml) or inhibiting (clone AIIB2, 1 µg/ml) antibodies. 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-g007: Wounded Sdc1−/− lung epithelium has attenuated repair with forced β1 integrin subunit activation.Wild-type and Sdc1−/− ALI cultures were injured in the presence of a control (rat isotype IgG, 1 µg/ml) or β1 integrin subunit activating (clone 9EG7, 1 µg/ml) or inhibiting (clone AIIB2, 1 µg/ml) antibodies. 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: Next, we wounded WT and Sdc1−/− ALI cultures in the presence of control, β1-activating, or β1-inhibiting antibodies (Figure 7). Inhibition of β1 integrins augmented wound closure rates of injured WT ALI cultures to levels equivalent to Sdc1−/− cultures. Conversely, forced activation of the β1 integrin subunit slowed the wound closure rate of injured Sdc1−/− ALI cultures to that of WT conditions. Congruous with our hypothesis, inhibiting β1 integrin subunit restored wound closure rate of Mmp7−/− cultures to WT levels (Figure 8). In WT ALI cultures, the activating β1 integrin antibody significantly slowed wound closure relative to control conditions, but this effect was seen at the higher concentration used (compare Figures 7 and 8). In contrast, the higher concentration of β1 integrin activating antibody had no effect on Mmp7−/− wound closure rate suggesting that the β1 integrin subunit was already maximally activated.


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 has attenuated repair with forced β1 integrin subunit activation.Wild-type and Sdc1−/− ALI cultures were injured in the presence of a control (rat isotype IgG, 1 µg/ml) or β1 integrin subunit activating (clone 9EG7, 1 µg/ml) or inhibiting (clone AIIB2, 1 µg/ml) antibodies. 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-g007: Wounded Sdc1−/− lung epithelium has attenuated repair with forced β1 integrin subunit activation.Wild-type and Sdc1−/− ALI cultures were injured in the presence of a control (rat isotype IgG, 1 µg/ml) or β1 integrin subunit activating (clone 9EG7, 1 µg/ml) or inhibiting (clone AIIB2, 1 µg/ml) antibodies. 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: Next, we wounded WT and Sdc1−/− ALI cultures in the presence of control, β1-activating, or β1-inhibiting antibodies (Figure 7). Inhibition of β1 integrins augmented wound closure rates of injured WT ALI cultures to levels equivalent to Sdc1−/− cultures. Conversely, forced activation of the β1 integrin subunit slowed the wound closure rate of injured Sdc1−/− ALI cultures to that of WT conditions. Congruous with our hypothesis, inhibiting β1 integrin subunit restored wound closure rate of Mmp7−/− cultures to WT levels (Figure 8). In WT ALI cultures, the activating β1 integrin antibody significantly slowed wound closure relative to control conditions, but this effect was seen at the higher concentration used (compare Figures 7 and 8). In contrast, the higher concentration of β1 integrin activating antibody had no effect on Mmp7−/− wound closure rate suggesting that the β1 integrin subunit was already maximally activated.

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