TNF-α from inflammatory dendritic cells (DCs)regulates lung IL-17A/IL-5 levels and neutrophilia versus eosinophilia during persistent fungal infection

摘要

Aspergillus fumigatus is commonly associated with allergic bron-chopulmonary aspergillosis in patients with severe asthma in which chronic airway neutrophilia predicts a poor outcome. We were able to recapitulate fungus-induced neutrophilic airway in- -flammation in a mouse model in our efforts to understand the underlying mechanisms. However, neutrophilia occurred in a mouse strain-selective fashion, providing us with an opportunity to perform a comparative study to elucidate the mechanisms involved. Here we show that TNF-α, largely produced by Ly6c~+CD11b~+ dendritic cells (DCs), plays a central role in promoting IL-17A from CD4~+ T cells and collaborating with it to induce airway neutrophilia. Compared with C57BL/6 mice, BALB/c mice displayed significantly more TNF-a-producing DCs and macrophages in the lung. Lung TNF-α levels were drastically reduced in CD11c-DTR BALB/c mice depleted of CD11c+ cells, and TNF-α-producing Ly6c~+CD11b~+ cells were abolished in Dectin-1~(-/-)and MyD88~(-/-) BALB/c mice. TNF-a deficiency itself blunted accumulation of inflammatory Ly6c~+CD11b~+ DCs. Also, lack of TNF-a decreased IL-17A but promoted IL-5 levels, switching inflammation from a neutrophil to eosinophil bias resembling that in C57BL/6 mice. The TNF-α~( low)DCs in C57BL/6 mice contained more NF-kB p50 homodimers, which are strong repressors of TNF-a transcription. Functionally, collaboration between TNF-α and IL-17A triggered significantly higher levels of the neutrophil che-moattractants keratinocyte cytokine and macrophage inflammatory protein 2 in BALB/c mice. Our study identifies TNF-α as a molecular switch that orchestrates a sequence of events in DCs and CD4 T cells that promote neutrophilic airway inflammation.