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

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Antigens-CD, CD4-Positive-T-Lymphocytes, Dendritic-Cells, Eosinophilia, Humans, Interleukin-17, Interleukin-5, Lung, Mice, Mice-Inbred-BALB-C, Mice-Inbred-C57BL, NF-kappa-B, Neutrophils, Pulmonary-Aspergillosis, Toll-Like-Receptor-2, Tumor-Necrosis-Factor-alpha

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Proc Natl Acad Sci U S A 2011; 108(13):5360-5.


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-alpha, 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-alpha-producing DCs and macrophages in the lung. Lung TNF-alpha levels were drastically reduced in CD11c-DTR BALB/c mice depleted of CD11c+ cells, and TNF-alpha-producing Ly6c(+)CD11b(+) cells were abolished in Dectin-1(-/-) and MyD88(-/-) BALB/c mice. TNF-alpha deficiency itself blunted accumulation of inflammatory Ly6c(+)CD11b(+) DCs. Also, lack of TNF-alpha decreased IL-17A but promoted IL-5 levels, switching inflammation from a neutrophil to eosinophil bias resembling that in C57BL/6 mice. The TNF-alpha(low) DCs in C57BL/6 mice contained more NF-kappaB p50 homodimers, which are strong repressors of TNF-alpha transcription. Functionally, collaboration between TNF-alpha 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-alpha as a molecular switch that orchestrates a sequence of events in DCs and CD4 T cells that promote neutrophilic airway inflammation.