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Human Airway Smooth Muscle Promotes Human Lung Mast Cell Survival, Proliferation, and Constitutive Activation: Cooperative Roles for CADM1, Stem Cell Factor, and IL-6¹

Fay Hollins^*, Davinder Kaur^*, Weidong Yang^*, Glenn Cruse^*, Ruth Saunders^*, Amanda Sutcliffe^*, Patrick Berger^2,*, Akihiko Ito, Christopher E. Brightling^3,* and Peter Bradding^3,4,*

^* Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester Medical School, United Kingdom; and Division of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan

The microlocalization of mast cells within specific tissue compartments is thought to be critical for the pathophysiology of many diverse diseases. This is particularly evident in asthma where they localize to the airway smooth muscle (ASM) bundles. Mast cells are recruited to the ASM by numerous chemoattractants and adhere through CADM1, but the functional consequences of this are unknown. In this study, we show that human ASM maintains human lung mast cell (HLMC) survival in vitro and induces rapid HLMC proliferation. This required cell-cell contact and occurred through a cooperative interaction between membrane-bound stem cell factor (SCF) expressed on ASM, soluble IL-6, and CADM1 expressed on HLMC. There was a physical interaction in HLMC between CADM1 and the SCF receptor (CD117), suggesting that CADM1-dependent adhesion facilitates the interaction of membrane-bound SCF with its receptor. HLMC-ASM coculture also enhanced constitutive HLMC degranulation, revealing a novel smooth muscle-driven allergen-independent mechanism of chronic mast cell activation. Targeting these interactions in asthma might offer a new strategy for the treatment of this common disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Department of Health/Medical Research Council Clinician Scientist Fellowship and Wellcome Senior Clinical Fellowship for C.E.B., and a PhD studentship cofunded by University of Leicester and Cambridge Antibody Technology for F.H.

Fay Hollins, Davinder Kaur, Weidong Yang, Glenn Cruse, Ruth Saunders, Amanda Sutcliffe, and Patrick Berger performed the research and analyzed and interpreted the data. Akihiko Ito generated the CADM1 Abs and contributed to the design of the research. Chris Brightling and Peter Bradding designed the research, and analyzed and interpreted the data. Fay Hollins and Peter Bradding drafted the manuscript. All authors modified and approved the final manuscript.

² Current address: Université Bordeaux 2, Institut National de la Santé et de la Recherche Médicale U885, Bordeaux, France.

³ C.E.B. and P.B. are cosenior authors.

⁴ Address correspondence and reprint requests to Prof. Peter Bradding, Institute for Lung Health, Clinical Sciences, Glenfield Hospital, Leicester, LE3 9QP, U.K. E-mail address: pbradding{at}hotmail.com

⁵ Abbreviations used in this paper: AHR, airway hyperresponsiveness; ASM, airway smooth muscle; HLMC, human lung mast cell; EB, eosinophilic bronchitis; SCF, stem cell factor; PI, propidium iodide; DAPI, 4',6-diamidino-2-phenylindole.

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