Dataset Information

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

SUBMITTER: Fei M

PROVIDER: S-EPMC3069210 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Fei Mingjian M Bhatia Shikha S Oriss Timothy B TB Yarlagadda Manohar M Khare Anupriya A Akira Shizuo S Saijo Shinobu S Iwakura Yoichiro Y Fallert Junecko Beth A BA Reinhart Todd A TA Foreman Oded O Ray Prabir P Kolls Jay J Ray Anuradha A

Proceedings of the National Academy of Sciences of the United States of America 20110314 13

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 involve ...[more]

PMID: 21402950

Similar Datasets

Project description:Ankylosing spondylitis (AS) is a chronic autoimmune inflammatory disease that mainly affects the axial and sacroiliac joints. Single-nucleotide polymorphisms (SNPs) in genes encoding cytokines have been associated with AS, which can interfere with the production of these cytokines and contribute to the development of AS. In order to contribute to a better understanding of the pathology of AS, our objective was to investigate a possible association of the IL10 -1082 A>G SNP (rs1800896) with AS and to evaluate the serum levels of TNF-α, IL-10, IL-17A, and IL-17F in AS patients and controls comparing them with their respective genotypes (TNF rs1800629, IL10 rs1800896, IL17A rs2275913, and IL17F rs763780). Patients and controls were selected from the Maringá University Hospital and the Maringá Rheumatism Clinic, in Paraná State, Southern Brazil, and they were diagnosed by the ASAS Criteria. In total, 149 patients and 169 controls were genotyped for the IL10 -1082 A>G polymorphism using a polymerase chain reaction with sequence specific primers (PCR-SSP); the measurement of TNF-α serum levels was performed through the immunofluorimetric test and IL-10, IL-17A, and IL-17F using an ELISA test. There was a high frequency of the IL10 -1082 G allele in AS patients compared with controls with an odds ratio of 1.83 and 95% confidence interval of 1.32 to 2.54, and a significant difference in the genotype frequencies of the IL10 -1082 A/G+G/G between patients and healthy controls, with an odds ratio of 3.01 and 95% confidence interval of 1.75 to 5.17. In addition, increased serum levels of IL-10 were observed in AS patients: 2.38 (IQR, 0.91) pg/ml compared with controls 1.72 (IQR 0.93) pg/ml (P = 0.01). Our results also showed an association between IL17F rs763780 C/T+T/T genotypes and increased serum levels of IL-17F in patients with AS and also in controls. We can conclude that patients with the A/G and G/G genotypes for -1082 A>G (rs1800896) in the IL10 gene are three times more likely to develop AS, that the serum level of IL-10 was higher in AS patients and that the IL17F rs763780 polymorphism can affect the levels of IL-17F in the serum of patients and controls in the same way.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets