Rationale: One of the immunopathological features of allergic inflammation is the infiltration of helper T type 2 (Th2) cells to the site of disease. Activation of innate pattern recognition receptors such as Toll-like receptors (TLRs) plays a critical role in helper T type 1 cell differentiation, yet their contribution to the generation of Th2 responses to clinically relevant aeroallergens remains poorly defined. Objectives: To determine the requirement for TLR2, TLR4, and the Toll/ IL-1 receptor domain adaptor protein MyD88 in a murine model of allergic asthma. Methods: Wild-type and factor-deficient (⁻/⁻) mice were sensitized intranasally to the common allergen house dust mite (HDM) and challenged 2 weeks later on four consecutive days. Measurements of allergic airway inflammation, T-cell cytokine production, and airway hyperreactivity were performed 24 hours later. Measurements and Main Results: Mice deficient in MyD88 were protected from the cardinal features of allergic asthma, including granulocytic inflammation, Th2 cytokine production and airway hyperreactivity. Although HDM activated NF-kB in TLR2- or TLR4-expressing HEκ cells, only in TLR4⁻/⁻ mice was the magnitude of allergic airway inflammation and hyperreactivity attenuated. The diminished Th2 response present in MyD88⁻/⁻ and TLR4⁻/⁻ mice was associated with fewer OX40 ligand–expressing myeloid dendritic cells in the draininglymph nodes during allergic sensitization. Finally, HDM-specific IL-17 production and airway neutrophilia were attenuated in MyD88⁻/⁻ but not TLR4⁻/⁻ mice. Conclusions: Together, these data suggest that Th2-andTh17-mediated inflammation generated on inhalational HDM exposure is differentially regulated by the presence of microbial products and the activation of distinct MyD88-dependent pattern recognition receptors.
American Journal of Respiratory and Critical Care Medicine Vol. 179, Issue 10, p. 883-893