TNF-α-induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in patients with eosinophilic or neutrophilic asthma
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.
|Keywords||Asthma, Dendritic cells, Neutrophils, TH17 cells, TH2 cells|
|Persistent URL||dx.doi.org/10.1016/j.jaci.2017.08.012, hdl.handle.net/1765/102347|
|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