Heleen Vroman1, Ingrid M Bergen1, Jennifer A C van Hulst1, Menno van Nimwegen1, Denise van Uden1, Martijn J Schuijs2, Saravanan Y Pillai1, Geert van Loo3, Hamida Hammad2, Bart N Lambrecht4, Rudi W Hendriks1, Mirjam Kool5. 1. Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands. 2. Inflammation Research Center, VIB, Ghent, Belgium; Department of Respiratory Medicine, Ghent University, Ghent, Belgium. 3. Inflammation Research Center, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. 4. Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands; Inflammation Research Center, VIB, Ghent, Belgium; Department of Respiratory Medicine, Ghent University, Ghent, Belgium. 5. Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands. Electronic address: m.kool@erasmusmc.nl.
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.
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.
Authors: Heleen Vroman; Denise van Uden; Ingrid M Bergen; Jennifer A C van Hulst; Melanie Lukkes; Geert van Loo; Björn E Clausen; Louis Boon; Bart N Lambrecht; Hamida Hammad; Rudi W Hendriks; Mirjam Kool Journal: Allergy Date: 2020-06-14 Impact factor: 13.146
Authors: Rafael Leite Dantas; Jana Freff; Oliver Ambrée; Eva C Beins; Andreas J Forstner; Udo Dannlowski; Bernhard T Baune; Stefanie Scheu; Judith Alferink Journal: Cells Date: 2021-04-19 Impact factor: 6.600
Authors: Sonia Ventura; Florencia Cano; Yashaswini Kannan; Felix Breyer; Michael J Pattison; Mark S Wilson; Steven C Ley Journal: J Exp Med Date: 2018-10-18 Impact factor: 14.307