Toll/IL-1 Signaling Is Critical for House Dust Mite-specific Th1 and Th2 Responses

作者：Phipps Simon; Lam Chuan En; Kaiko Gerard E; Foo Shen Yun; Collison Adam; Mattes Joerg; Barry Jessica; Davidson Sophia; Oreo Kevin; Smith Lauren; Mansell Ashley; Matthaei Klaus I; Foster Paul S^*

来源：American Journal of Respiratory and Critical Care Medicine, 2009, 179(10): 883-893.

DOI：10.1164/rccm.200806-974OC

• asthma
• innate immunity
• eosinophil
• neutrophil

Rationale: One of the immunopathological features of allergic inflammation is the infiltrationof 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 I 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-kappa B in TLR2- or TLR4-expressing HEK 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 draining lymph 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- and Th17-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.

• 出版日期2009-5-15
• 单位河北医科大学