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TNF-α-induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in eosinophilic or neutrophilic asthma

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Abstract
Background: It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in T(H)2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with T(H)17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both T(H)2 and T(H)17 cell differentiation and is mediated through nuclear factor kappa B activation. Ablation of TNF-alpha-induced protein 3 (TNFAIP3), one of the crucial negative regulators of nuclear factor kappa B 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 T(H)2- and T(H)17-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 T(H)17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wild-type mice had a purely T(H)2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific T(H)17 cell differentiation through increased expression of the T(H)17-instructing cytokines IL-1 beta, IL-6, and IL-23, whereas HDM-specific T(H)2 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 T(H)2/T(H)17 cell differentiation. This implies that reducing DC activation could be a new pharmacologic intervention to treat patients with severe asthma who present with T(H)17-mediated neutrophilic inflammation.
Keywords
CD4(+) T-CELLS, NF-KAPPA-B, DUST MITE ALLERGEN, AIRWAY INFLAMMATION, IN-VIVO, INHALED ANTIGEN, TH2 RESPONSES, OX40 LIGAND, CROSS-TALK, EXPRESSION, Asthma, T(H)2 cells, T(H)17 cells, dendritic cells, neutrophils

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Chicago
Vroman, Heleen, Ingrid M Bergen, Jennifer AC van Hulst, Menno van Nimwegen, Denise van Uden, Martijn Schuijs, Saravanan Y Pillai, et al. 2018. “TNF-α-induced Protein 3 Levels in Lung Dendritic Cells Instruct TH2 or TH17 Cell Differentiation in Eosinophilic or Neutrophilic Asthma.” Journal of Allergy and Clinical Immunology 141 (5): 1620–1633.
APA
Vroman, H., Bergen, I. M., van Hulst, J. A., van Nimwegen, M., van Uden, D., Schuijs, M., Pillai, S. Y., et al. (2018). TNF-α-induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in eosinophilic or neutrophilic asthma. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 141(5), 1620–1633.
Vancouver
1.
Vroman H, Bergen IM, van Hulst JA, van Nimwegen M, van Uden D, Schuijs M, et al. TNF-α-induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in eosinophilic or neutrophilic asthma. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. 2018;141(5):1620–33.
MLA
Vroman, Heleen et al. “TNF-α-induced Protein 3 Levels in Lung Dendritic Cells Instruct TH2 or TH17 Cell Differentiation in Eosinophilic or Neutrophilic Asthma.” JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 141.5 (2018): 1620–1633. Print.
@article{8564401,
  abstract     = {Background: It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in T(H)2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with T(H)17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both T(H)2 and T(H)17 cell differentiation and is mediated through nuclear factor kappa B activation. Ablation of TNF-alpha-induced protein 3 (TNFAIP3), one of the crucial negative regulators of nuclear factor kappa B 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 T(H)2- and T(H)17-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 T(H)17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wild-type mice had a purely T(H)2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific T(H)17 cell differentiation through increased expression of the T(H)17-instructing cytokines IL-1 beta, IL-6, and IL-23, whereas HDM-specific T(H)2 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 T(H)2/T(H)17 cell differentiation. This implies that reducing DC activation could be a new pharmacologic intervention to treat patients with severe asthma who present with T(H)17-mediated neutrophilic inflammation.},
  author       = {Vroman, Heleen and Bergen, Ingrid M and van Hulst, Jennifer AC and van Nimwegen, Menno and van Uden, Denise and Schuijs, Martijn and Pillai, Saravanan Y and van Loo, Geert and Hammad, Hamida and Lambrecht, Bart and Hendriks, Rudi W and Kool, Mirjam},
  issn         = {0091-6749},
  journal      = {JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY},
  keywords     = {CD4(+) T-CELLS,NF-KAPPA-B,DUST MITE ALLERGEN,AIRWAY INFLAMMATION,IN-VIVO,INHALED ANTIGEN,TH2 RESPONSES,OX40 LIGAND,CROSS-TALK,EXPRESSION,Asthma,T(H)2 cells,T(H)17 cells,dendritic cells,neutrophils},
  language     = {eng},
  number       = {5},
  pages        = {1620--1633},
  title        = {TNF-α-induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in eosinophilic or neutrophilic asthma},
  url          = {http://dx.doi.org/10.1016/j.jaci.2017.08.012},
  volume       = {141},
  year         = {2018},
}

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