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

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 5

Tlr6–/– DCs have an impaired ability to regulate Th17 cell expansion due to impaired IL-23 levels.

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Tlr6–/– DCs have an impaired ability to regulate Th17 cell expansion du...
(A) Number of CD3+CD4+ cells expressing intracellular IFN-γ, IL-4, IL-17, or foxp3 in LN from WT and Tlr6–/– mice at day 30 after conidia challenge. (B) Percentage of IL-17A–producing cells in coculture of CD11c+ and CD4+ cells isolated from spleen of WT, Tlr6–/–, or Tlr6–/– mice treated with rIL-23. †††P < 0.05 compared with the cocultures of WT DCs and Tlr6–/– CD4 T cells. (C) Transcript expression of Il6, Tgfb1, and Tnf in BMDCs from WT naive mice stimulated in vitro with medium alone or rIL-23, rIL-12, or LPS. (D) Percentage of DCs and AMO or IMO expressing IL-23 receptor in naive lungs. (E) Percentage of bead-isolated CD11c cells expressing CD11b, MHCII, and LAP–TGF-β in lungs from WT and Tlr6–/– mice at day 21 after conidia challenge cultured either with medium alone or A. fumigatus antigen (Ag). Data represent 2 independent experiments and show mean ± SEM of n = 5 mice/group. *P < 0.05 compared with WT under the same conditions or medium.