Environmental bioaerosol antigen Methanosphaera stadtmanae induces a TH17 inflammatory lung response via TLR4 signaling

Abstract Bioaerosols in occupational environments are highly associated with the development of inflammatory lung diseases. The archaea specie Methanosphaera stadtmanae (MSS) is found in high concentrations in poultries, dairy farms and swine confinement buildings bioaerosols (up to 108 archaea/m3). MSS induces a strong specie-dependent inflammatory lung response in mice, characterized by T cells, eosinophils, neutrophils, and IgG production. However, the polarity of lung response induced by MSS and the mechanisms underlying this inflammatory response remain unknown. Using a mouse model, we show that MSS induced a weak TH2 (CD4+/IL-13+T cells) strong TH17 (CD4+/IL-17A+T cells) lung response, characterized by IgG1 (but not IgG2a and IgE) production. Moreover, mice did not develop airway hyperresponsiveness following MSS exposure. Interestingly, increasing MSS quantity led to a lower eosinophil count associated with a decreased TH2 response. Using transgenic mice, we found that eosinophils, mast cells and ILC2 cells are not required for the TH2 and TH17 inflammatory response to MSS. However, Tlr4−/− mice (but not Tlr2−/−) had reduced airway inflammation compared to WT mice after exposure to MSS, indicating a crucial role for TLR4 activation in this specific response. Finally, heat denaturation and zymography studies suggested TLR4 activation likely occurs through MSS protein antigen recognition rather than by enzymatic activity and cell damage. We conclude that MSS induces a TH17 inflammatory lung response via TLR4 signaling.