The Therapeutic Potential of Toll-Like Receptor 7 Stimulation in Asthma

Abstract

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.

Safety and pharmacodynamics of intranasal GSK2245035, a TLR7 agonist for allergic rhinitis: A randomized trial

“…Toll‐like receptor 7 (natural ligand viral ssRNA) is of particular relevance for respiratory allergies . TLR7 polymorphism has been strongly linked with susceptibility to asthma and other atopic disorders .…”

Fatty Acid-Mimetic Micelles for Dual Delivery of Antigens and Imidazoquinoline Adjuvants

“…This result contrasts previous reports implicating IMQ as a Th1-type adjuvant 19 and as a therapeutic for mitigating Th2-driven allergy and asthma in the airways. 96 The Th2-biased antibody response in the study may reflect incomplete or insufficient IgG class switching due to the lack of a booster vaccination and/or the time point at which antibody titers were measured. Indeed, using a nanoparticle-based vaccine loaded with IMQ, a shift in IgG1/IgG2a ratio to less than unity was previously reported following three IN vaccinations over 28 weeks.…”

Toll-like receptors, triggering receptor expressed on myeloid cells family members and receptor for advanced glycation end-products in allergic airway inflammation

“…Adoptive transfer of TLR competent pDCs was shown to block these exaggerated inflammatory responses and increase IFN-γ release [94]. Studies using synthetic TLR7 ligands (R837 and R848) have shown that activation of the receptor prevented airway hyper-responsiveness, eosinophilic infiltration and goblet cell hyperplasia in an ovalbumin model of asthma [95]. There were also decreased levels of IL-5 and LTB4 in bronchoalveolar lavage fluid, suggesting that TLR7 dampens allergic airway responses [36].…”