TLR7 ligand prevents allergen-induced airway hyperresponsiveness and eosinophilia in allergic asthma by a MYD88-dependent and MK2-independent pathway.
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 T(H)2 to T(H)1, 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.
Moisan
J
J
Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
Camateros
P
P
Thuraisingam
T
T
Marion
D
D
Koohsari
H
H
Martin
P
P
Boghdady
M L
ML
Ding
A
A
Gaestel
M
M
Guiot
M C
MC
Martin
J G
JG
Radzioch
D
D
D048868:Adaptor Proteins, Signal Transducing / Q000494:pharmacology*; D000402:Airway Obstruction / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D000485:Allergens; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D007093:Imidazoles / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011804:Quinolines / Q000627:therapeutic use; D051199:Toll-Like Receptor 7 / Q000187:drug effects / Q000502:physiology*; D000099190:MAP-Kinase-Activated Kinase 2
D048868:Adaptor Proteins, Signal Transducing; D000485:Allergens; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011804:Quinolines; D051199:Toll-Like Receptor 7; D000099190:MAP-Kinase-Activated Kinase 2; C507780:Myd88 protein, mouse; C477038:Tlr7 protein, mouse