CD151, a laminin receptor showing increased expression in asthmatic patients, contributes to airway hyperresponsiveness through calcium signaling

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• 作者：Yongkang Qiao ; MSc^a ; John Kit Chung Tam ; MD^b ; Sheryl S.L. Tan ; PhD^a ; Yee Kit Tai ; PhD^a ; Chin Yein Chin ; MSc^a ; Alastair G. Stewart ; PhD^c ; Leonie Ashman ; PhD^d ; Kiyotoshi Sekiguchi ; PhD^e ; Shenna Y. Langenbach ; BSc^c ; Gerald Stelmack ; MSc^f ; ^g ; Andrew J. Halayko ; PhD^f ; ^g ; Thai Tran ; PhD^a ; ^{tran_thai@nuhs.edu.sg} ; on behalf of the Melbourne Epidemiological Study of Childhood Asthma group
• 关键词：Airway hyperresponsiveness ; airway smooth muscle ; asthma ; contraction ; calcium ; CD151 ; G protein&ndash ; coupled receptor ; integrins ; laminin ; PKC ; tetraspanin
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：139
• 期：1
• 页码：82-92.e5
• 全文大小：4019 K
• 卷排序：139

文摘

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.ObjectiveWe sought to ascertain whether CD151 expression is clinically relevant to asthma and whether CD151 expression affects AHR.MethodsUsing 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.ResultsThe 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.ConclusionsWe 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.