title: TNF-alpha from inflammatory dendritic cells (DCs) regulates lung IL-17A/IL-5 levels and neutrophilia versus eosinophilia during persistent fungal infection.
abstract: 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-α(low) 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.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Mingjian
authors.initials: M
authors.lastname: Fei
authors.forename: Shikha
authors.initials: S
authors.lastname: Bhatia
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Oriss
authors.forename: Manohar
authors.initials: M
authors.lastname: Yarlagadda
authors.forename: Anupriya
authors.initials: A
authors.lastname: Khare
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Shinobu
authors.initials: S
authors.lastname: Saijo
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fallert Junecko
authors.forename: Todd A
authors.initials: TA
authors.lastname: Reinhart
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.forename: Prabir
authors.initials: P
authors.lastname: Ray
authors.forename: Jay
authors.initials: J
authors.lastname: Kolls
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ray
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004802:Eosinophilia / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D015848:Interleukin-5 / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D055732:Pulmonary Aspergillosis / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D020381:Interleukin-17; D015848:Interleukin-5; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha