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Am J Physiol Lung Cell Mol Physiol 290: L987-L995, 2006. First published December 16, 2005; doi:10.1152/ajplung.00440.2005
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TLR7 ligand prevents allergen-induced airway hyperresponsiveness and eosinophilia in allergic asthma by a MYD88-dependent and MK2-independent pathway

J. Moisan,1 P. Camateros,1 T. Thuraisingam,3,5 D. Marion,1 H. Koohsari,1 P. Martin,1 M. L. Boghdady,1 A. Ding,2 M. Gaestel,3 M. C. Guiot,4 J. G. Martin,1 and D. Radzioch1,5

1McGill University, Department of Experimental Medicine, Montreal, Quebec, Canada; 2Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York; 3Medical School Hannover, Institute of Biochemistry, Hannover, Germany; 4McGill University, Department of Pathology, Montreal Neurological Hospital, Montreal, Quebec, Canada; and 5McGill University, Department of Human Genetics, Montreal, Quebec, Canada

Submitted 12 October 2005 ; accepted in final form 14 December 2005

Asthma is one of the leading causes of childhood hospitalization, and its incidence is on the rise throughout the world. Currently, the standard treatment for asthma is the use of corticosteroids to try to suppress the inflammatory reaction taking place in the bronchial tree. Using a murine model of atopic allergic asthma employing a methacholine-hyperresponsive (A/J) as well as a hyporesponsive (C57BL/6) strain of mice sensitized and challenged with ovalbumin, we show that treatment with a synthetic Toll-like receptor 7 (TLR7) ligand (S-28463, a member of the imidazoquinoline family) prevents development of the asthmatic phenotype. Treatment with S-28463 resulted in a reduction of airway resistance and elastance following ovalbumin sensitization and challenge. This was accompanied by a dramatic reduction in infiltration of leukocytes, especially eosinophils, into the lungs of both C57BL/6 and A/J mice following OVA challenge. Treatment with S-28463 also abolished both the elevation in serum IgE level as well as the induction of IL-4, IL-5, and IL-13 by OVA challenge. The protective effects of S-28463 were also observed in MK2 knockout, but not MYD88 knockout, mice. We did not observe a switch in cytokine profile from TH2 to TH1, as both IL-12p70 and IFN-{gamma} levels were reduced following S-28463 treatment. These results clearly demonstrate the anti-inflammatory effect of imidazoquinolines in an allergic asthma model as well as the clinical potential of TLR7 ligands in the treatment of allergic diseases.

Toll-like receptors; asthma; eosinophils; lung; inflammation; mitogen-activated protein kinase-activated protein-2


Address for reprint requests and other correspondence: D. Radzioch, Montreal General Hospital Research Institute, 1650 Cedar Ave. L11-218, Montreal, Quebec, H3G 1A4, Canada (e-mail: danuta.radzioch{at}muhc.mcgill.ca)




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