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Published ahead of print on February 4, 2005, doi:10.1164/rccm.200409-1220OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 10, May 2005, 1103-1108

A more recent version of this article appeared on May 15, 2005
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Submitted on September 16, 2004
Accepted on January 25, 2005

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

Christopher E Brightling1*, Alaina J Ammit2, Davinder Kaur1, Judith L Black2, Andrew J Wardlaw1, J Margaret Hughes2, and Peter Bradding1

1 Institute for Lung Health, Department of Infection, Inflammation and Immunity, Leicester-Warwick Medical School and University Hospitals of Leicester, Leicester, United Kingdom, 2 Respiratory Research Group, Faculty of Pharmacy and Department of Pharmacology, University of Sydney, Sydney, Australia

* To whom correspondence should be addressed. E-mail: ceb17{at}le.ac.uk.

Mast cell microlocalisation within the airway smooth muscle bundle is an important determinant of the asthmatic phenotype. We hypothesised that mast cells migrate towards airway smooth muscle in response to smooth muscle-derived chemokines. In this study we investigated: i) chemokine receptor expression by mast cells in the airway smooth muscle bundle in bronchial biopsies from subjects with asthma using immunohistology, ii) the concentration of chemokines in supernatants from stimulated ex vivo airway smooth muscle cells from subjects with and without asthma measured by ELISA and iii) mast cell migration towards 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 to 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 to those from healthy controls. These results suggest that inhibition of the CXCL10/CXCR3 axis offers a novel target for the treatment of asthma.
Key words: mast cells, chemokine receptors, airway smooth muscle, chemotaxis, chemokines




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