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

Abstract

Toll-like receptor (TLR) mediated signaling 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 proinflammatory responses. Mice were immunized on day 0, 14 and 21 by intrapericoneal 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 1 mg/kg) were administered intratracheally 1 h 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-1 beta, IL-6, and TNF-alpha 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-gamma and IL-10 or associated with increased numbers of Foxp3(+)CD4(+) 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

A New Era of Targeting the Ancient Gatekeepers of the Immune System: Toll-Like Agonists in the Treatment of Allergic Rhinitis and Asthma

“…Resiquimod or R848 or S28463 (3M Pharmaceutics, Maplewood, Minn., USA; mechanism-based studies, level 5 of evidence) is a TLR7/8 agonist, the systemic [25,89,100,101] or intranasal [96] application of which has been shown to suppress AHR and airway remodeling in murine models of asthma with similar dose responses [96,100,101,102,103]. Resiquimod administration suppressed acute asthma with a shifting of the immune response toward Th1 and type-1 IFN production, a reduction in both Th1 and Th2 cytokine levels in the lungs of rats and mice, and a reduction in lung eosinophilia, goblet cell hyperplasia and total IgE levels [96,100,101,102,103].…”

“…Resiquimod administration suppressed acute asthma with a shifting of the immune response toward Th1 and type-1 IFN production, a reduction in both Th1 and Th2 cytokine levels in the lungs of rats and mice, and a reduction in lung eosinophilia, goblet cell hyperplasia and total IgE levels [96,100,101,102,103]. Despite consistency regarding suppression the of Th2 response, some studies report that it can suppress Th1 responses in vivo in allergic asthma in mice and rats [101].…”

“…Synthetic TLR9 agonists reduced airway eosinophilia, IL-4, IL-5 and IgE production, and enhanced IL-10 levels in bronchoalveolar lavage fluid of murine models of asthma [102,109,111]. Furthermore, they inhibited airway remodeling by reducing airway collagen deposition, metalloproteinase activity and angiogenesis [112,113,114,115].…”

ICOS-Expressing CD4 T Cells Induced via TLR4 in the Nasal Mucosa Are Capable of Inhibiting Experimental Allergic Asthma

“…Administration of TLR2 or TLR4 ligands into the lower airways carries the potential danger of exacerbating lower airway inflammation by promoting monocytic/neutrophilic inflammation (22). Alternatively, the nasal mucosa is populated by lymphoid tissues (23), as well as the recently described M cells (24), which can serve as effective inductive sites for immune responses, while minimizing exposure of the lower airways to TLR ligands.…”

Severity of Allergic Airway Disease Due to House Dust Mite Allergen Is Not Increased after Clinical Recovery of Lung Infection with Chlamydia pneumoniae in Mice

“…Twenty-four hours after the last HDM allergen challenge, pulmonary function was measured invasively in anesthetized, spontaneously breathing mice (performed at the Fraunhofer Institute for Toxicology and Experimental Medicine [ITEM], Hannover, Germany) to assess AHR as described previously (38,39). Briefly, pulmonary resistance (R L ) was calculated from the measured differences in transpulmonary pressure and tidal respiratory flow by body plethysmography (type 871; HSE-Harvard Apparatus, March-Hugstetten, Germany) under isoflurane anesthesia in orotracheally intubated animals (by HEM 4.2 software; Notocord Systems, Croissy, France).…”