Background: It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in TH2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with TH17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both TH2 and TH17 cell differentiation and is mediated through nuclear factor κB activation. Ablation of TNF-α-induced protein 3 (TNFAIP3), one of the crucial negative regulators of nuclear factor κB activation in myeloid cells and DCs, was shown to control DC activation. Objective: In this study we investigated the precise role of TNFAIP3 in myeloid cells for the development of TH2- and TH17-cell mediated asthma. Methods: We exposed mice with conditional deletion of the Tnfaip3 gene in either myeloid cells (by using the lysozyme M [LysM] promotor) or specifically in DCs (by using the Cd11c promotor) to acute and chronic house dust mite (HDM)-driven asthma models. Results: We demonstrated that reduced Tnfaip3 gene expression in DCs in either Tnfaip3 CD11c or Tnfaip3 LysM mice dose-dependently controlled development of TH17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wild-type mice had a purely TH2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific TH17 cell differentiation through increased expression of the TH17-instructing cytokines IL-1β, IL-6, and IL-23, whereas HDM-specific TH2 cell differentiation was hampered by increased IL-12 and IL-6 production. Conclusions: These data show that the extent of TNFAIP3 expression in DCs controls TH2/TH17 cell differentiation. This implies that reducing DC activation could be a new pharmacologic intervention to treat patients with severe asthma who present with TH17-mediated neutrophilic inflammation.

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Keywords Asthma, Dendritic cells, Neutrophils, TH17 cells, TH2 cells
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Journal Journal of Allergy and Clinical Immunology
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/304221 - Immune regulation of NF-kappaB in Dendritic Cell subsets by the ubiquitin editing enzyme A20 (A20 DC SUBSETS)
Vroman, H, Bergen, I.M, van Hulst, J.A.C. (Jennifer A.C.), van Nimwegen, M, van Uden, D. (Denise), Schuijs, M.J, … Kool, M. (2017). TNF-α-induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in patients with eosinophilic or neutrophilic asthma. Journal of Allergy and Clinical Immunology. doi:10.1016/j.jaci.2017.08.012