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CCL11 and GM-CSF Differentially Use the Rho GTPase Pathway to Regulate Motility of Human Eosinophils in a Three-Dimensional Microenvironment¹

Michelle J. Muessel^*, Karen S. Scott^*, Peter Friedl, Peter Bradding^* and Andrew J. Wardlaw^2,*

^* Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; and Department of Dermatology and Rudolph Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany

Asthma is a common disease that causes considerable morbidity. Increased numbers of airway eosinophils are a hallmark of asthma. Mechanisms controlling the entry of eosinophils into asthmatic lung have been intensively investigated, but factors regulating migration within the tissue microenvironment are less well understood. We modeled this by studying chemoattractant and growth factor-mediated human eosinophil migration within a three-dimensional collagen matrix. Stimulation with GM-CSF induced dose-dependent, random migration with a maximum of 77 ± 4.7% of cells migrating. In contrast, CCL11 and C5a caused a more modest although significant degree of migration (19 ± 1.8% and 20 ± 2.6%, respectively). Migration to GM-CSF was partially dependent on Ca²⁺ and _Mβ₂ integrins. The Rho family of small GTPases regulates intracellular signaling of cell migration. GM-CSF-induced migration was only partially dependent on Rho kinase/Rho-associated kinase (ROCK) and was independent of RhoA activation. In contrast, CCL11-induced migration was fully dependent on both RhoA and ROCK. Activation of RhoA was therefore neither necessary nor sufficient to cause eosinophil migration in a three-dimensional collagen environment. This study suggests that eosinophil growth factors are likely to be required for eosinophil migration within the bronchial mucosa, and this involves signal transduction pathways distinct from those used by G protein-associated chemoattractants.

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 by a grant from Asthma U.K. to A.J.W.

² Address correspondence and reprint requests to Dr. Andrew J. Wardlaw, Department of Respiratory Medicine, Glenfield Hospital, Groby Road, Leicester LE3 9QP, U.K. E-mail address: aw24{at}le.ac.uk

³ Abbreviations used in this paper: 3D, three dimensional; 2D, two dimensional; LPA, lysophosphatydic acid; MMP, matrix metalloproteinase; ROCK, Rho-associated kinase.

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