Toll‐like receptor 6 drives interleukin‐17A expression during experimental hypersensitivity pneumonitis

SummaryHypersensitivity 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 ofSaccharopolyspora 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 withS. 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.