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Free Content Toll-like receptor 6 drives interleukin-17A expression during experimental hypersensitivity pneumonitis

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Summary

Hypersensitivity pneumonitis (HP) is a T-cell-driven disease that is histologically characterized by diffuse mononuclear cell infiltrates and loosely formed granulomas in the lungs. We have previously reported that interleukin-17A (IL-17A) contributes to the development of experimental HP, and that the pattern recognition receptor Toll-like receptor 6 (TLR6) might be a factor in the initiation of this response. Using a well-established murine model of Saccharopolyspora rectivirgula-induced HP, we investigated the role of TLR6 in the immunopathogenesis of this disease. In the absence of TLR6 signalling, mice that received multiple challenges with S.¬†rectivirgula-antigen (SR-Ag) had significantly less lung inflammation compared with C57BL/6 mice (wild-type; WT) similarly challenged with SR-Ag. Flow cytometric analysis of whole lung samples from SR-Ag-challenged mice showed that TLR6−/− mice had a decreased CD4+ : CD8+ T-cell ratio compared with WT mice. Cytokine analysis at various days after the final SR-Ag challenge revealed that whole lungs from TLR6−/− mice contained significantly less IL-17A than lungs from WT mice with HP. The IL-17A-driving cytokines IL-21 and IL-23 were also expressed at lower levels in SR-Ag-challenged TLR6−/− mice, when compared with SR-Ag-challenged WT mice. Other pro-inflammatory cytokines, namely interferon-γ and RANTES, were also found to be regulated by TLR6 signalling. Anti-TLR6 neutralizing antibody treatment of dispersed lung cells significantly impaired SR-Ag-induced IL-17A and IL-6 generation. Together, these results indicate that TLR6 plays a pivotal role in the development and severity of HP via its role in IL-17A production.
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Keywords: Toll-like receptor-6; hypersensitivity pneumonitis; interleukin-17A

Document Type: Research Article

Affiliations: 1: Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA 2: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Publication date: May 1, 2010

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