Integrin α2β1 regulates collagen I tethering to modulate hyperresponsiveness in reactive airway disease models
Sean Liu, … , Dean Sheppard, Aparna B. Sundaram
Sean Liu, … , Dean Sheppard, Aparna B. Sundaram
Published May 6, 2021
Citation Information: J Clin Invest. 2021;131(12):e138140. https://doi.org/10.1172/JCI138140.
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Research Article Muscle biology Pulmonology

Integrin α2β1 regulates collagen I tethering to modulate hyperresponsiveness in reactive airway disease models

Abstract

Severe asthma remains challenging to manage and has limited treatment options. We have previously shown that targeting smooth muscle integrin α5β1 interaction with fibronectin can mitigate the effects of airway hyperresponsiveness by impairing force transmission. In this study, we show that another member of the integrin superfamily, integrin α2β1, is present in airway smooth muscle and capable of regulating force transmission via cellular tethering to the matrix protein collagen I and, to a lesser degree, laminin-111. The addition of an inhibitor of integrin α2β1 impaired IL-13–enhanced contraction in mouse tracheal rings and human bronchial rings and abrogated the exaggerated bronchoconstriction induced by allergen sensitization and challenge. We confirmed that this effect was not due to alterations in classic intracellular myosin light chain phosphorylation regulating muscle shortening. Although IL-13 did not affect surface expression of α2β1, it did increase α2β1-mediated adhesion and the level of expression of an activation-specific epitope on the β1 subunit. We developed a method to simultaneously quantify airway narrowing and muscle shortening using 2-photon microscopy and demonstrated that inhibition of α2β1 mitigated IL-13–enhanced airway narrowing without altering muscle shortening by impairing the tethering of muscle to the surrounding matrix. Our data identified cell matrix tethering as an attractive therapeutic target to mitigate the severity of airway contraction in asthma.

Authors

Sean Liu, Uyen Ngo, Xin-Zi Tang, Xin Ren, Wenli Qiu, Xiaozhu Huang, William DeGrado, Christopher D.C. Allen, Hyunil Jo, Dean Sheppard, Aparna B. Sundaram

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Figure 5

Inhibition of integrin α2β1 impairs airway narrowing without altering smooth muscle shortening.

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Inhibition of integrin α2β1 impairs airway narrowing without altering sm...
(A) Schematic of configuration for imaging with 2-photon microscopy. Tracheal rings from α-SMA–RFP mice were treated for 12 hours with IL-13 (100 ng/mL) or saline, and then for 1 hour with c15 (10 μg/mL), Y-27632 (100 μM), or vehicle, followed by imaging at baseline and after methacholine (Mch, 10–4 M). (B) Representative transverse views of trachea and quantification of decrease in airway area after methacholine relative to baseline. Single scale bar: 150 μm; asterisk scale bar: 100 μm. (C) Representative coronal views of posterior smooth muscle from rings in B showing α-SMA (red) and collagen fibrils and tissue autofluorescence (green), as well as quantification of decrease in muscle area and volume after methacholine relative to baseline. Scale bar: 100 μm. n = 5 rings per group. **P < 0.01, ***P < 0.001, ****P < 0.0001 compared with IL-13/vehicle; 2-way ANOVA with Tukey’s multiple-comparison test. Data are the mean ± SEM.