Toll-like receptors (TLRs) mediate pathogen recognition in the respiratory system, but TLR activation has both beneficial and deleterious effects during asthma. Clinical data demonstrates that TLR6 is an example of a pattern recognition receptor that exerts protective effects in clinical asthma. To explore the mechanism through which TLR6 expression by immune and inflammatory cells mediates this effect, we investigated its role in a murine model of Aspergillus fumigatus-induced chronic asthma. TLR6-/- mice with fungal asthma exhibited significantly increased airway hyperresponsiveness, inflammation, and remodeling compared with WT asthmatic groups. Surprisingly, whole lung levels of IL-23 and IL-17 were significantly lower in TLR6-/- versus WT asthmatic mice. TLR6-/- DCs generated significantly less IL-23 upon activation with either lipopolysaccharide or zymosan. Impaired IL-23 generation in TLR6-/- mice also corresponded with significantly lower dectin-1 expression and Th17 expansion both in vivo and in vitro. Exogenous IL-23 treatment of asthmatic TLR6-/- mice in vivo restored IL-17A production and significantly reduced airway hyperresponsiveness, inflammation, and lung fungal burden compared with untreated asthmatic TLR6-/- mice. Together, we demonstrate that TLR6 activation is critical for IL-23 and Th17, and both regulate the allergic inflammatory response during fungal asthma.
- Copyright © 2011 by The American Association of Immunologists, Inc.