Toll-like receptor 6 drives interleukin-17A expression during experimental hypersensitivity pneumonitis.
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-gamma 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.
Fong
Daniel J
DJ
Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.
Hogaboam
Cory M
CM
Matsuno
Yosuke
Y
Akira
Shizuo
S
Uematsu
Satoshi
S
Joshi
Amrita D
AD
D000542:Alveolitis, Extrinsic Allergic / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016930:Saccharopolyspora / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051216:Toll-Like Receptor 6 / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; C098680:Il17a protein, mouse; D020381:Interleukin-17; C495369:Tlr6 protein, mouse; D051216:Toll-Like Receptor 6