Toll-like receptor 7 rapidly relaxes human airways

Matthew G. Drake, Gregory D. Scott, Becky J. Proskocil, Allison D. Fryer, David B. Jacoby, Elad H. Kaufman

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Rationale: 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. Objectives: Tocharacterize TLR7 expression and TLR7-inducedairway 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. Measurements and Main Results: The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation ofmethacholine-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.

Original languageEnglish (US)
Pages (from-to)664-672
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume188
Issue number6
DOIs
StatePublished - Sep 15 2013

Keywords

  • Asthma
  • Imiquimod
  • Nerve
  • Nitric oxide
  • Toll-like receptor 7

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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