TNF-?–induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in eosinophilic or neutrophilic asthma - 04/05/18
Abstract |
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 Tnfaip3CD11c or Tnfaip3LysM 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.
Le texte complet de cet article est disponible en PDF.Key words : Asthma, TH2 cells, TH17 cells, dendritic cells, neutrophils
Abbreviations used : AHR, BAL, BM, cDC, DC, HDM, LysM, MeV, MLN, moDC, NF-κB, RNA-seq, T-bet, TCR, TNFAIP3, WT, YFP
Plan
Supported in part by NWO-VENI (916.11.067), the European Framework Program 7 (FP7-MC-CIG grant 304221.), and The Netherlands Lung Foundation (3.2.12.087 and 4.2.13.054JO). |
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Disclosure of potential conflict of interest: H. Vroman received travel support from the Dutch Respiratory Society. M. Kool has salary support grants from The Netherlands Lung Foundation, a VENI grant from the Dutch Foundation for Sciences, an institutional grant from FP7 Marie Curie CIG, and pending institutional grants from the Dutch Heart Foundation and Dutch Arthritis Foundation. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 141 - N° 5
P. 1620 - mai 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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