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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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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.
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.
Chicago author-date
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.
Chicago author-date (all authors)
Vroman, Heleen, Ingrid M Bergen, Jennifer AC van Hulst, Menno van Nimwegen, Denise van Uden, Martijn Schuijs, Saravanan Y Pillai, Geert van Loo, Hamida Hammad, Bart Lambrecht, Rudi W Hendriks, and Mirjam Kool. 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.
IEEE
[1]
H. Vroman 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, vol. 141, no. 5, pp. 1620–1633, 2018.
@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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