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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 13; pp. 5360 - 5365
• Main Authors: Fei, Mingjian, Bhatia, Shikha, Oriss, Timothy B., Yarlagadda, Manohar, Khare, Anupriya, Akira, Shizuo, Saijo, Shinobu, Iwakura, Yoichiro, Junecko, Beth A. Fallert, Reinhart, Todd A., Foreman, Oded, Ray, Prabir, Kolls, Jay, Ray, Anuradha, Beutler, Bruce
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29-03-2011; National Acad Sciences
• Subjects: Animals; Antigens, CD - immunology; Aspergillus fumigatus; Asthma; Biological Sciences; CD4-Positive T-Lymphocytes - immunology; Conidia; Dendritic cells; Dendritic Cells - immunology; Eosinophilia - immunology; Eosinophils; Epithelial cells; Humans; Inflammation; Interleukin-17 - immunology; Interleukin-5 - immunology; Lung - cytology; Lung - immunology; Lungs; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neutrophils; Neutrophils - immunology; NF-kappa B - metabolism; Pulmonary Aspergillosis - immunology; Toll-Like Receptor 2 - immunology; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1015476108

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-⁺-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-α low DCs in C57BL/6 mice contained more NF-қB 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.