The therapeutic potential of Toll-like receptor 7 stimulation in asthma.
Asthma is an inflammatory disorder of the airways frequently characterized by an excessive Th2 adaptive immune response. Activation of Toll-like receptor (TLR)-7, a single-stranded viral RNA receptor that is highly expressed in the airways, triggers a rapid innate immune response and favors a subsequent Th1 response. Because of this role in pulmonary immunoregulation, TLR7 has gained considerable interest as a therapeutic target in asthma. Synthetic TLR7 ligands, including the imidazoquinolines imiquimod (R837) and resiquimod (R848), and 8-hydroxyadenine derivatives have been developed for other clinical indications. TLR7 activation prevents ovalbumin-induced airway hyperreactivity, eosinophilic inflammation, goblet cell hyperplasia and airway remodeling in murine models of asthma. TLR7 activation also inhibits viral replication in the lung and prevents virus-induced airway hyperreactivity. Furthermore, it has recently been shown that stimulating TLR7 rapidly relaxes airway smooth muscle, dilating the airways. This bronchodilating effect, which occurs in seconds to minutes and depends on rapid production of nitric oxide, indicates that TLR7 can signal via previously unrecognized pathways. The effects of decreasing the allergic Th2 response, acting as an immediate bronchodilator, and promoting an antiviral immune environment, make TLR7 an attractive drug target. We examine the current understanding of TLR7 as a therapeutic target and its translation to asthma treatment in humans.
Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon, USA.
Matthew G
MG
Drake
Elad H
EH
Kaufman
Allison D
AD
Fryer
David B
DB
Jacoby
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009569:Nitric Oxide / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism*
D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D051199:Toll-Like Receptor 7; D009569:Nitric Oxide