title: Neutralizing TNFα restores glucocorticoid sensitivity in a mouse model of neutrophilic airway inflammation.
abstract: Asthma is a heterogeneous disorder, evidenced by distinct types of inflammation resulting in different responsiveness to therapy with glucocorticoids (GCs). Tumor necrosis factor α (TNFα) is involved in asthma pathogenesis, but anti-TNFα therapies have not proven broadly effective. The effects of anti-TNFα treatment on steroid resistance have never been assessed. We investigated the role of TNFα blockade using etanercept in the responsiveness to GCs in two ovalbumin-based mouse models of airway hyperinflammation. The first model is GC sensitive and T helper type 2 (Th2)/eosinophil driven, whereas the second reflects GC-insensitive, Th1/neutrophil-predominant asthma subphenotypes. We found that TNFα blockade restores the therapeutic effects of GCs in the GC-insensitive model. An adoptive transfer indicated that the TNFα-induced GC insensitivity occurs in the non-myeloid compartment. Early during airway hyperinflammation, mice are GC insensitive specifically at the level of thymic stromal lymphopoietin (Tslp) transcriptional repression, and this insensitivity is reverted when TNFα is neutralized. Interestingly, TSLP knockout mice displayed increased inflammation in the GC-insensitive model, suggesting a limited therapeutic application of TSLP-neutralizing antibodies in subsets of patients suffering from Th2-mediated asthma. In conclusion, we demonstrate that TNFα reduces the responsiveness to GCs in a mouse model of neutrophilic airway inflammation. Thus antagonizing TNFα may offer a new strategy for therapeutic intervention in GC-resistant asthma.
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Dejager
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Dendoncker
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Eggermont
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Souffriau
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Van Hauwermeiren
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Willart
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Van Wonterghem
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Naessens
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Ballegeer
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Vandevyver
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Respiratory Medicine, Ghent University, Ghent, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Hammad
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Respiratory Medicine, Ghent University, Ghent, Belgium.|Department Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Lambrecht
authors.affiliation: Cytokine Receptor Laboratory, Department of Medical Protein Research, VIB, Ghent, Belgium.|Cytokine Receptor Lab, Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: De Bosscher
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Grooten
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Libert
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D001249:Asthma / Q000276:immunology*; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000187:drug effects*; D000068800:Etanercept / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006967:Hypersensitivity / Q000276:immunology*; D007118:Immunoassay; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D016133:Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018927:Anti-Asthmatic Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept