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The CXCL10/CXCR3 Axis Mediates Human Lung Mast Cell Migration to Asthmatic Airway Smooth Muscle

Institute for Lung Health, Department of Infection, Inflammation and Immunity, Leicester-Warwick Medical School and University Hospitals of Leicester, Leicester, United Kingdom; and Respiratory Research Group, Faculty of Pharmacy and Department of Pharmacology, University of Sydney, Australia

Correspondence and requests for reprints should be addressed to C. E. Brightling, Ph.D., University Hospitals of Leicester, Groby Road, Leicester LE3 9QP, UK. E-mail: ceb17{at}le.ac.uk

Mast cell microlocalization within the airway smooth muscle bundle is an important determinant of the asthmatic phenotype. We hypothesized that mast cells migrate toward airway smooth muscle in response to smooth muscle–derived chemokines. In this study, we investigated (1) chemokine receptor expression by mast cells in the airway smooth muscle bundle in bronchial biopsies from subjects with asthma using immunohistology, (2) the concentration of chemokines in supernatants from stimulated ex vivo airway smooth muscle cells from subjects with and without asthma measured by enzyme-linked immunosorbent assay, and (3) mast cell migration toward these supernatants using chemotaxis assays. We found that CXCR3 was the most abundantly expressed chemokine receptor on human lung mast cells in the airway smooth muscle in asthma and was expressed by 100% of these mast cells compared with 47% of mast cells in the submucosa. Human lung mast cell migration was induced by airway smooth muscle cultures predominantly through activation of CXCR3. Most importantly, CXCL10 was expressed preferentially by asthmatic airway smooth muscle in bronchial biopsies and ex vivo cells compared with those from healthy control subjects. These results suggest that inhibition of the CXCL10/CXCR3 axis offers a novel target for the treatment of asthma.

Key Words: airway smooth muscle • chemokine receptors • chemokines • chemotaxis • mast cells

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