Regulation of actin dynamics by WNT-5A: implications for human airway smooth muscle contraction.

Tim Koopmans,Kuldeep Kumawat,Reinoud Gosens,Andrew J Halayko

doi:10.1038/srep30676

Tim Koopmans, Kuldeep Kumawat + Show 2 more

Open Access

https://doi.org/10.1038/srep30676

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Abstract

A defining feature of asthma is airway hyperresponsiveness (AHR), which underlies the exaggerated bronchoconstriction response of asthmatics. The role of the airway smooth muscle (ASM) in AHR has garnered increasing interest over the years, but how asthmatic ASM differs from healthy ASM is still an active topic of debate. WNT-5A is increasingly expressed in asthmatic ASM and has been linked with Th2-high asthma. Due to its link with calcium and cytoskeletal remodelling, we propose that WNT-5A may modulate ASM contractility. We demonstrated that WNT-5A can increase maximum isometric tension in bovine tracheal smooth muscle strips. In addition, we show that WNT-5A is preferentially expressed in contractile human airway myocytes compared to proliferative cells, suggesting an active role in maintaining contractility. Furthermore, WNT-5A treatment drives actin polymerisation, but has no effect on intracellular calcium flux. Next, we demonstrated that WNT-5A directly regulates TGF-β1-induced expression of α-SMA via ROCK-mediated actin polymerization. These findings suggest that WNT-5A modulates fundamental mechanisms that affect ASM contraction and thus may be of relevance for AHR in asthma.

Highlights

Asthma is a disease characterized by chronic inflammation of the large and small airways, and estimated to affect 235 million people worldwide[1]
We have shown that WNT-5A protein expression is increased in airway smooth muscle (ASM) cells isolated from asthmatics compared to non-asthmatic individuals[23] and WNT-5A expression has been associated with Th2-high asthma[24]
In this study we explored the role of non-canonical WNT signalling, focusing on the well-studied family member WNT-5A, in the regulation of cytoskeletal reorganization, mobilization of intracellular calcium and airway smooth muscle contraction

Summary

Introduction

Asthma is a disease characterized by chronic inflammation of the large and small airways, and estimated to affect 235 million people worldwide[1]. Not all studies have reproduced this finding in whole ASM tissue[2,4,8], suggesting that the mechanical properties of the surrounding extracellular tissue matrix may be altered in asthma. In this regard it is notable that the ASM of asthmatics does appear to respond differently to strain induced by tidal breathing. We provide evidence that this is mediated by rearranging actin filaments, as we found that in cultured human ASM cells, WNT-5A increases the F/G-actin actin, while no changes in expression of alpha-smooth muscle actin (α-SMA) or [Ca2+] handling were evident. We found that WNT-5A knock down attenuates TGF-β1-induced α-SMA expression and that exogenous WNT-5A synergistically increased TGF-β1-induced α-SMA expression in human ASM cells

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