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The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A
Ana Paula Moreira, … , Shizuo Akira, Cory M. Hogaboam
Ana Paula Moreira, … , Shizuo Akira, Cory M. Hogaboam
Published October 17, 2011
Citation Information: J Clin Invest. 2011;121(11):4420-4432. https://doi.org/10.1172/JCI44999.
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Research Article Immunology

The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A

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Abstract

TLRs are a family of receptors that mediate immune system pathogen recognition. In the respiratory system, TLR activation has both beneficial and deleterious effects in asthma. For example, clinical data indicate that TLR6 activation exerts protective effects in asthma. Here, we explored the mechanism or mechanisms through which TLR6 mediates this effect using mouse models of Aspergillus fumigatus–induced and house dust mite antigen–induced (HDM antigen–induced) chronic asthma. Tlr6–/– mice with fungal- or HDM antigen–induced asthma exhibited substantially increased airway hyperresponsiveness, inflammation, and remodeling compared with WT asthmatic groups. Surprisingly, whole-lung levels of IL-23 and IL-17 were markedly lower in Tlr6–/– versus WT asthmatic mice. Tlr6–/– DCs generated less IL-23 upon activation with lipopolysaccharide, zymosan, or curdlan. Impaired IL-23 generation in Tlr6–/– mice also corresponded with lower levels of expression of the pathogen-recognition receptor dectin-1 and expansion of Th17 cells both in vivo and in vitro. Exogenous IL-23 treatment of asthmatic Tlr6–/– mice restored IL-17A production and substantially reduced airway hyperresponsiveness, inflammation, and lung fungal burden compared with that in untreated asthmatic Tlr6–/– mice. Together, our data demonstrate that TLR6 activation is critical for IL-23 production and Th17 responses, which both regulate the allergic inflammatory response in chronic fungal-induced asthma. Thus, therapeutics targeting TLR6 activity might prove efficacious in the treatment of clinical asthma.

Authors

Ana Paula Moreira, Karen A. Cavassani, Ugur B. Ismailoglu, Rikki Hullinger, Michael P. Dunleavy, Darryl A. Knight, Steven L. Kunkel, Satoshi Uematsu, Shizuo Akira, Cory M. Hogaboam

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Figure 1

TLR6 expression in asthmatic lungs.

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TLR6 expression in asthmatic lungs.
TLR6 expression (red) was evaluated ...
TLR6 expression (red) was evaluated using immunofluorescence in normal lungs (B) or in the lungs of asthmatic patients with severe disease (C). Nuclei stained with DAPI (blue) in all photomicrographs and isotype control are demonstrated in A. Arrows indicate the presence of TLR6. Original magnification, ×400. Photomicrographs are representative of 6 different normal or 6 different asthmatic lungs.

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