Toll-like receptor 7 activation reduces the contractile response of airway smooth muscle.
Viral respiratory infections are a major cause of asthma exacerbations. The mechanisms by which such infections aggravate airway inflammation and hyperresponsiveness are complex and not fully understood. Toll-like receptor 7 is particularly relevant in the defence against common respiratory viruses, as it recognizes single-stranded viral RNA. The present study was designed to investigate the effect of Toll-like receptor 7 stimulation on airway smooth muscle reactivity. The presence of Toll-like receptor 7 within guinea pig airways was ensured with immunohistochemistry. The effects induced by 3days of culture of tracheal segments with the Toll-like receptor 7 agonist R837 or the Toll-like receptor 7/8 agonist R848 were evaluated in a myograph organ bath system. The intracellular mechanisms involved were dissected using inhibitors of intracellular mitogen-activated protein kinase (MAPK) activity. Toll-like receptor 7 immunoreactivity was observed across the epithelial cell layer and in the airway smooth muscle cells. Treatment with R837 and R848 reduced the airway contractile responses to 5-hydroxytryptamine (5-HT). This effect was abolished upon treatment with inhibitors of the p38 MAPK pathway and nuclear factor (NF)-κB pathways. According to the present model, activation of Toll-like receptor 7 might prevent development of airway hyperresponsiveness by acting on the airway smooth muscle. The presented data support the idea that individuals with defect Toll-like receptor 7 function might be more prone to respond to virus infections with asthmatic exacerbations. Further, they suggest that inhaled Toll-like receptor 7 ligand might be an effective treatment alternative for asthma.
Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. Anna-Karin.ekman@ki.se
Anna-Karin
AK
Ekman
Mikael
M
Adner
Lars-Olaf
LO
Cardell
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000627:therapeutic use; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use*; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
C557465:1-(2-methylpropyl)-1H-imidazo(4,5-c)quinolin 4-amine; D007093:Imidazoles; D016328:NF-kappa B; D011804:Quinolines; D051199:Toll-Like Receptor 7; D020930:MAP Kinase Kinase Kinases; C402365:resiquimod