Toll-like receptor 7 rapidly relaxes human airways.
BACKGROUND
Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs.


OBJECTIVE
To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs.


METHODS
Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs.


RESULTS
The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways.


CONCLUSIONS
TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma.
1 Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon; and.
Matthew G
MG
Drake
Gregory D
GD
Scott
Becky J
BJ
Proskocil
Allison D
AD
Fryer
David B
DB
Jacoby
Elad H
EH
Kaufman
D000704:Analysis of Variance; D000818:Animals; D004804:Eosinophils / Q000276:immunology / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D006168:Guinea Pigs; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D009126:Muscle Relaxation / Q000276:immunology* / Q000502:physiology; D009130:Muscle, Smooth / Q000276:immunology* / Q000502:physiology; D020545:Respiratory Mucosa / Q000276:immunology / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000276:immunology* / Q000502:physiology; D051200:Toll-Like Receptor 8 / Q000276:immunology / Q000502:physiology; D014132:Trachea / Q000276:immunology* / Q000502:physiology
D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8