TLR agonist mediated suppression of allergic responses is associated with increased innate inflammation in the airways

Matthias J. Düchs , Christian Hahn , Ewald Benediktus , Melanie Werner-Klein , Armin Braun (1) , Hans Gerd Hoymann (1) , Florian Gantner , Klaus J. Erb

1 Fraunhofer ITEM - Fraunhofer Institute for Toxicology and Experimental Medicine

Toll-like receptor (TLR) mediated signalling induces pro-inflammatory responses and can both suppress and exacerbate allergic responses in the airways. The aim of our study was to directly compare the efficacy of different TLR agonists in inhibiting or exacerbating the development of Th2-mediated responses in the airways and investigate if the suppressive effects were associated with increased pro-inflammatory responses. Mice were immunized on day 0, 14 and 21 by intraperitoneal injection of ovalbumin/alum and exposed to ovalbumin aerosol on day 26 and 27. TLR2-, TLR3-, TLR4-, TLR7- and TLR9 agonists (0.001, 0.01, 0.1, or 1mg/kg) were administered intratracheally 1h before each allergen exposure. Both the TLR7- and TLR9 agonists dose dependently reduced airway eosinophilia, while the TLR3 agonist only reduced airway eosinophilia at a dose of 1.0 mg/kg. The TLR2- and TLR4 agonists potentiated eosinophilia. All TLR agonists enhanced neutrophil numbers at doses as low as 0.01 mg/kg, in particular TLR2- and TLR4 agonists. TLR7- and TLR9 agonists also significantly reduced IL-4 and IL-5 levels and all TLR agonists, with the exception of TLR7, enhanced the amount IL-1ß, IL-6, and TNF-α detected in the whole lung lavage. Only application of TLR9 agonist induced detectable levels of IL-10 in the lung. Suppressive effects of the TLR agonists were not dependent upon IFN-γ and IL-10 or associated with increased numbers of Foxp3CD4 Tr cells in the lavage fluid. Airway resistance was reduced significantly only when TLR7 agonist was administered. When applied therapeutically 2 days after allergen exposure, all TLR agonists, except TLR2, similarly reduced airway eosinophilia and IL-4 levels. Taken together our results show that TLR7 agonists had the strongest anti-asthmatic effects with the lowest pro-inflammatory potential, suggesting that activating TLR7 may have the greatest potential to treat allergic disorders in humans.

Mots clés: mouse; asthma; allergy; eosinophils; neutrophils; TLR-agonists; innate-inflammation

Domaines: Pneumologie et système respiratoire

Matthias J. Düchs, Christian Hahn, Ewald Benediktus, Melanie Werner-Klein, Armin Braun, et al.. TLR agonist mediated suppression of allergic responses is associated with increased innate inflammation in the airways. Pulmonary Pharmacology & Therapeutics, 2011, 24 (2), pp.203. ⟨10.1016/j.pupt.2010.12.009⟩. ⟨hal-00724891⟩