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

By Mingjian Fei, Shikha Bhatia, Timothy B. Oriss, Manohar Yarlagadda, Anupriya Khare, Shizuo Akira, Shinobu Saijo, Yoichiro Iwakura, Beth A. Fallert Junecko, Todd A. Reinhart, Oded Foreman, Prabir Ray, Jay Kolls and Anuradha Ray


Aspergillus fumigatus is commonly associated with allergic bronchopulmonary aspergillosis in patients with severe asthma in which chronic airway neutrophilia predicts a poor outcome. We were able to recapitulate fungus-induced neutrophilic airway inflammation 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-α–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-α deficiency itself blunted accumulation of inflammatory Ly6c+CD11b+ DCs. Also, lack of TNF-α decreased IL-17A but promoted IL-5 levels, switching inflammation from a neutrophil to eosinophil bias resembling that in C57BL/6 mice. The TNF-αlow DCs in C57BL/6 mice contained more NF-κB p50 homodimers, which are strong repressors of TNF-α transcription. Functionally, collaboration between TNF-α and IL-17A triggered significantly higher levels of the neutrophil chemoattractants 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

Topics: Biological Sciences
Publisher: National Academy of Sciences
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Provided by: PubMed Central
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