Immunomodulatory Effects of Viral TLR Ligands on Experimental Asthma Depend on the Additive Effects of IL-12 and IL-10

Abstract

Based on epidemiological data, the hygiene hypothesis associates poor hygienic living conditions during childhood with a lower risk for the development of allergic diseases such as bronchial asthma. The role of viral infections, and especially of viral TLR ligands, within this context remains to be clarified. Viral TLR ligands involve dsRNA and ssRNA which are recognized by TLR-3 or TLR-7, respectively. In this study, we evaluated the impact of TLR-3 or TLR-7 activation on experimental asthma in mice. Systemic application of the synthetic TLR-3 or TLR-7 ligands polycytidylic-polyinosinic acid (p(I:C)) or R-848, respectively, during the sensitization phase prevented the production of OVA-specific IgE and IgG1 Abs and subsequently abolished all features of experimental asthma including airway hyperresponsiveness and allergic airway inflammation. Furthermore, administration of p(I:C) or R-848 to animals with already established primary allergic responses revealed a markedly reduced secondary response following allergen aerosol rechallenges. In contrast to wild-type animals, application of p(I:C) or R-848 to IL-12p35−/− mice had no effect on airway inflammation, goblet cell hyperplasia, and airway hyperresponsiveness. However, in the absence of IL-12, the numbers of eosinophils and lymphocytes in bronchoalveolar lavage fluids were still significantly reduced. These partial effects could also be abolished by neutralizing anti-IL-10 Abs in IL-12p35−/− mice. These data indicate that TLR-3 or TLR-7 activation by viral TLR ligands has both preventive as well as suppressive effects on experimental asthma which is mediated by the additive effects of IL-12 and IL-10.

TLR3 but Not TLR7/8 Ligand Induces Allergic Sensitization to Inhaled Allergen

“…Most studies have investigated the effects of bacterial or viral compounds on allergic diseases when administered either during systemic sensitization or to already sensitized animals prior to allergen challenge. Systemic application of R848 or poly(I:C) during allergen sensitization results in reduction of allergic airway disease after allergen challenge (36). In addition, systemic treatment of sensitized animals during primary challenge (37) or during secondary Ag challenge (36) again reduced allergic airway disease.…”

“…For intracellular cytokine analysis, we used allophycocyanin-labeled IFN-g (BD Pharmingen), PE-labeled IL-17A (BD Pharmingen), and PE-labeled IL-5 (BD Pharmingen). Abs were incubated at 4˚C for [30][31][32][33][34][35][36][37][38][39][40] ), single-cell suspensions of tracheal lymph nodes or lung cells were adjusted and surface stained for PeCy7-labeled CD4 PeCy7 and PE-labeled CD25 (all BD Pharmingen) as described. Foxp3 staining was performed following the advice of the manufacturer of the fixation/permeabilization set (eBioscience).…”

Contribution of IL-33–activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice

“…This finding is quite different from our case, that S. venezuelensis infection induces IL-33-dependent eosinophilia. We suspected that this discrepancy could come from IL-10 production in influenza virus-infected mice because IL-10 is shown to inhibit eosinophil accumulation (31,32). Pulmonary eosinophilia is a very common complication of helminth infections, such as Strongyloides, Ascaris, Toxocara, and Ancylostoma species (33).…”

Role of Toll-like receptors in the development of allergic inflammation in asthma

“…Therefore, systemic application of the synthetic ligands for TLR3 and TLR7 protects against the development of asthmatic symptoms and reduces the symptoms already present such as allergic airway inflammation and airway hyperresponsiveness [15].…”