TNF-α produced by inflammatory DCs as a molecular switch in Th17/Th2 and neutrophilic/eosinophilic responses during persistent fungal infection (103.2)

• Published in: The Journal of immunology (1950) 2011-04, Vol.186 (1_Supplement), p.103-103.2
• Main Authors: Fei, Mingjian, Bhatia, Shikha, Oriss, Timothy, Yarlagadda, Manohar, Khare, Anupriya, Akira, Shizuo, Iwakura, Yoichiro, Ray, Prabir, Kolls, Jay, Ray, Anuradha
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.186.Supp.103.2

Aspergillus fumigatus is associated with allergic bronchopulmonary aspergillosis, a pulmonary allergic disorder, in which neutrophilia predicts a poor outcome. In our efforts to recapitulate fungus-induced airway neutrophilia in the allergic setting, we found that similar exposure to the fungus resulted in a neutrophil-dominated response in BALB/c mice but an eosinophil-biased response in C57BL/6 mice. By performing a comparative study, we identified TNF-α as the key mediator that skewed the response towards neutrophilia but away from eosinophilia. Between the two strains, TNF-αhigh CD11b+ Ly6C+ DCs were more abundant in the lungs of WT BALB/c mice which was compromised in MyD88-/-, dectin-1-/- and TNF-α-/- mice. As compared to TNF-αhigh Balb/c-DCs, TNF-αlow C57BL/6-DCs contained more NF-B p50 homodimers as strong repressors of TNF-α transcription. Lower TNF-α accounted for lower TLR2 levels on C57BL/6 DCs impairing collaboration between TLR2 and Dectin-1 in augmenting TNF-α via a positive feedback loop. Functionally, in Balb/c mice, the high level of TNF-α enhanced Th17 responses and in collaboration with IL-17A upregulated the neutrophil chemoattractants KC and MIP-2. Conversely, the lungs of C57BL/6 or TNF-α-/- mice showed higher IL-5 levels and therefore an eosinophil-rich response. Our study for the first time highlights a central role of TNF-α as a molecular switch that regulates the neutrophil/eosinophil balance in airway inflammation.