The Mfge8‐α8β1;1‐PTEN pathway regulates airway smooth muscle contraction in allergic inflammation

Abstract

Asthma affects ∼300 million people worldwide. Despite multiple treatment options, asthma treatment remains unsatisfactory in a subset of patients. Airway obstruction is a hallmark of allergic asthma and is largely due to airway smooth muscle hypercontractility induced by airway inflammation. Identification of molecular pathways that regulate airway smooth muscle hypercontractility is of considerable therapeutic interest. We previously identified roles for milk fat globule epidermal growth factor-like 8 (Mfge8) in opposing the effects of allergic inflammation on increasing airway smooth muscle contractile force. In this study, we delineate the signaling pathway by which Mfge8 mediates these effects. By using genetic and pharmacologic approaches, we show that the α8β1 integrin and the phosphatase and tensin homolog (PTEN) mediate the effects of Mfge8 on preventing IL-13-induced increases in airway contractility. Tracheal rings from mice with smooth muscle-specific deletion of α8β1 or PTEN have enhanced contraction in response to treatment with IL-13. Enhanced IL-13-induced tracheal ring contraction in Mfge8 mice was abolished by treatment with the PI3K inhibitor. Mechanistically, IL-13 induces ubiquitination and degradation of PTEN protein. Our findings identify a role for the Mfge8-α8β1-PTEN pathway in regulating the force of airway smooth muscle contraction in the setting of allergic inflammation.-Khalifeh-Soltani, A., Gupta, D., Ha, A., Podolsky, M. J., Datta, R., Atabai, K. The Mfge8-α8β1-PTEN pathway regulates airway smooth muscle contraction in allergic inflammation.

Induced hepatic stellate cell integrin, α8β1, enhances cellular contractility and TGFβ activity in liver fibrosis

“…Our findings illuminated previously unknown characteristics of α8β1: de novo expression in activated HSCs in vitro and in vivo , upregulation of αSMA, and TGFβ activation on HSCs and fibroblasts. These findings fit well with previous observations of Itga8 expression in other contractile cells, including airway [15] and gastric [16] smooth muscle cells, arrector pili [17] and sensory hair cells [18]. Recent single‐cell RNA‐sequencing data from NASH mice revealed exclusive Itga8 expression in HSCs in liver cells [19].…”

Detecting the Multiomics Signatures of Factor-Specific Inflammatory Effects on Airway Smooth Muscles

“…MAST4 is a part of the PTEN signaling pathway (Valiente et al, 2005;Sotelo et al, 2012), which has been confirmed to mediate the IL-13-induced stimulation, hyper-responsiveness, and inflammation, of airway smooth muscles, thus validating this predicted target gene (Jiang et al, 2012). Similar conclusions have also been further validated in later studies (Hu et al, 2014;Khalifeh-Soltani et al, 2018). Therefore, MAST4 is definitely correlated with the interleukinmediated stimulation of airway smooth muscles.…”

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

“…Notably, our mechanistic studies suggest that these effects did not occur through modulation of actin-myosin cross-bridge interactions, but rather by modulating cellular tethering to the extracellular matrix. Members of the integrin family have previously been described to have effects on airway hyperresponsiveness (21,22) by modulating intracellular pathways resulting in downstream regulation of myosin light chain phosphorylation, including interaction with SSAT and PTEN. However, there is a growing body of evidence supporting the role of independently regulated cellular processes, including cytoskeletal stabilization (23,24), matrix stiffness (25,26), and intercellular tethering (27,28), in modulating force transmission throughout smooth muscle bundles.…”