Differential Roles of CXCL2 and CXCL3 and Their Receptors in Regulating Normal and Asthmatic Airway Smooth Muscle Cell Migration

1. Laila A. Al-Alwan*,1, 
2. Ying Chang*,1, 
3. Andrea Mogas*, 
4. Andrew J. Halayko†,
5. Carolyn J. Baglole*, 
6. James G. Martin*, 
7. Simon Rousseau*, 
8. David H. Eidelman* and
9. Qutayba Hamid*

+Author Affiliations

1. ^*Meakins-Christie Laboratories and Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada; and
2. ^†Department of Physiology, University of Manitoba, Respiratory Hospital, Winnipeg, Manitoba R3A 1R8, Canada

1. Address correspondence and reprint requests to Dr. Qutayba Hamid, Meakins-Christie Laboratories and Respiratory Division, Department of Medicine, McGill University, 3626 Rue St. Urbain, Montreal, Quebec H2X 2P2, Canada. E-mail address:Qutayba.Hamid@McGill.ca

1. ↵1 L.A.A.-A. and Y.C. contributed equally to this work.

Abstract

Structural cell migration plays a central role in the pathophysiology of several diseases, including asthma. Previously, we established that IL-17–induced (CXCL1, CXCL2, and CXCL3) production promoted airway smooth muscle cell (ASMC) migration, and consequently we sought to investigate the molecular mechanism of CXC-induced ASMC migration. Recombinant human CXCL1, CXCL2, and CXCL3 were used to assess migration of human primary ASMCs from normal and asthmatic subjects using a modified Boyden chamber. Neutralizing Abs or small interfering RNA (siRNA) knockdown and pharmacological inhibitors of PI3K, ERK1/2, and p38 MAPK pathways were used to investigate the receptors and the signaling pathways involved in CXC-induced ASMC migration, respectively. We established the ability of CXCL2 and CXCL3, but not CXCL1, to induce ASMC migration at the tested concentrations using normal ASMCs. We found CXCL2-induced ASMC migration to be dependent on p38 MAPK and CXCR2, whereas CXCL3-induced migration was dependent on p38 and ERK1/2 MAPK pathways via CXCR1 and CXCR2. While investigating the effect of CXCL2 and CXCL3 on asthmatic ASMC migration, we found that they induced greater migration of asthmatic ASMCs compared with normal ones. Interestingly, unlike normal ASMCs, CXCL2- and CXCL3-induced asthmatic ASMC migration was mainly mediated by the PI3K pathway through CXCR1. In conclusion, our results establish a new role of CXCR1 in ASMC migration and demonstrate the diverse mechanisms by which CXCL2 and CXCL3 mediate normal and asthmatic ASMC migration, suggesting that they may play a role in the pathogenesis of airway remodeling in asthma.

This Article

1. Published online before printJuly 31, 2013, doi: 10.4049/​jimmunol.1203421The Journal of Immunology
   September 1, 2013 vol. 191 no. 5 2731-2741

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Footnotes

• This work was supported by the Canadian Institutes of Health Research, the American Thoracic Society, the Costello Memorial Fund, and the McGill University Health Centre–Research Institute of Fonds de la Recherche en Santé du Québec.
• The online version of this article contains supplemental material.
• Abbreviations used in this article:

  ASMC

  airway smooth muscle cell

  GRO

  growth-related oncogene

  PDGF-BB

  platelet-derived growth factor subunit B

  siRNA

  small interfering RNA.

• Received December 14, 2012.
• Accepted July 3, 2013.

• Copyright © 2013 by The American Association of Immunologists, Inc.

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