Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
J Allergy Clin Immunol. 2017 Jan;139(1):82-92.e5. doi: 10.1016/j.jaci.2016.03.029. Epub 2016 Apr 27.
Airway smooth muscle (ASM) contraction underpins airway constriction; however, underlying mechanisms for airway hyperresponsiveness (AHR) remain incompletely defined. CD151, a 4-transmembrane glycoprotein that associates with laminin-binding integrins, is highly expressed in the human lung. The role of CD151 in ASM function and its relationship to asthma have yet to be elucidated.
We sought to ascertain whether CD151 expression is clinically relevant to asthma and whether CD151 expression affects AHR.
Using immunohistochemical analysis, we determined the expression of CD151 in human bronchial biopsy specimens from patients with varying asthma severities and studied the mechanism of action of CD151 in the regulation of ASM contraction and bronchial caliber in vitro, ex vivo, and in vivo.
The number of CD151 ASM cells is significantly greater in patients with moderate asthma compared with those in healthy nonasthmatic subjects. From loss- and gain-of-function studies, we reveal that CD151 is required for and enhances G protein-coupled receptor (GPCR)-induced peak intracellular calcium release, the primary determinant of excitation-contraction coupling. We show that the localization of CD151 can also be perinuclear/cytoplasmic and offer an explanation for a novel functional role for CD151 in supporting protein kinase C (PKC) translocation to the cell membrane in GPCR-mediated ASM contraction at this site. Importantly, CD151 mice are refractory to airway hyperreactivity in response to allergen challenge.
We identify a role for CD151 in human ASM contraction. We implicate CD151 as a determinant of AHR in vivo, likely through regulation of GPCR-induced calcium and PKC signaling. These observations have significant implications in understanding the mechanism for AHR and the efficacy of new and emerging therapeutics.
气道平滑肌（ASM）收缩是气道收缩的基础；然而，气道高反应性（AHR）的潜在机制仍不完全明确。CD151 是一种 4 次跨膜糖蛋白，与层粘连蛋白结合的整合素相关，在人肺中高度表达。CD151 在 ASM 功能中的作用及其与哮喘的关系尚未阐明。
我们旨在确定 CD151 的表达是否与哮喘有临床相关性，以及 CD151 的表达是否影响 AHR。
我们通过免疫组织化学分析，确定了不同哮喘严重程度患者的支气管活检标本中 CD151 的表达，并研究了 CD151 在调节 ASM 收缩和支气管管径中的作用机制，包括在体外、离体和体内。
与健康非哮喘患者相比，中度哮喘患者的 CD151 ASM 细胞数量明显增加。通过失活和激活功能研究，我们揭示了 CD151 是 G 蛋白偶联受体（GPCR）诱导的细胞内钙释放的必需因子，也是兴奋-收缩偶联的主要决定因素。我们还发现 CD151 的定位也可以是核周/细胞质，并为 CD151 在支持蛋白激酶 C（PKC）易位到细胞膜在 GPCR 介导的 ASM 收缩中的新功能作用提供了解释，这在该部位起作用。重要的是，CD151 小鼠对过敏原刺激的气道高反应性无反应。
我们确定了 CD151 在人类 ASM 收缩中的作用。我们将 CD151 作为体内 AHR 的决定因素，可能是通过调节 GPCR 诱导的钙和 PKC 信号。这些观察结果对理解 AHR 的机制以及新出现的治疗方法的疗效具有重要意义。
