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SR-Ag-induced IL-17 plays a pivotal role in the immunopathology of HP and targeting IL-17 is an attractive therapeutic option for this disease.

The present study addressed the modulatory role of CC chemokine receptor 4 (CCR4) in Tolllike receptor (TLR) 9-mediated innate immunity and explored the underlying molecular mechanisms. Our results demonstrated that CCR4-deficient mice were resistant to both septic peritonitis induced by cecal ligation and puncture (CLP) and CpG DNA/Dgalactosamine-induced shock. In bone marrow-derived macrophages (BMMU) from CLPtreated CCR4-deficient mice, TLR9-mediated pathways of MAPK/AP-1, PI3K/Akt, and IjB kinase (IKK)/NF-jB were impaired compared to wild-type (WT) cells. While TLR9 expression was not altered, the intensity of internalized CpG DNA was increased in CCR4-deficient macrophages when compared to WT macrophages. Pharmacological inhibitor studies revealed that impaired activation of JNK, PI3K/Akt, and/or IKK/NF-jB could be responsible for decreased proinflammatory cytokine expression in CCR4-deficient macrophages. Interestingly, the CCR4-deficient BMMU exhibited an alternatively activated (M2) phenotype and the impaired TLR9-mediated signal transduction responses in CCR4-deficient cells were similar to the signaling responses observed in WT BMMU skewed to an alternatively activated phenotype. These results indicate that macrophages deficient in CCR4 impart a regulatory influence on TLR9-mediated innate immunity.

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 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 TLR6mice 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 SRAg-challenged WT mice. Other pro-inflammatory cytokines, namely interferon-c 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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