Therapeutic suppression of pulmonary neutrophilia and allergic airway hyperresponsiveness by an RORγt inverse agonist
| Autor: | Donald N. Cook, Gentaro Izumi, Seddon Y. Thomas, Alexander Medvedev, Hideki Nakano, Hong Soon Kang, Gregory S. Whitehead, Keiko Nakano, Anton M. Jetten, Tadeusz P Karcz, Sergei S. Makarov |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Inflammation Allergic sensitization Mice 03 medical and health sciences 0302 clinical medicine RAR-related orphan receptor gamma Hypersensitivity Respiratory Hypersensitivity medicine Animals Inverse agonist Receptor Lung Asthma business.industry Interleukin-17 Dust Pneumonia General Medicine Nuclear Receptor Subfamily 1 Group F Member 3 respiratory system medicine.disease Neutrophilia respiratory tract diseases Mice Inbred C57BL Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Immunology Th17 Cells medicine.symptom Airway business Research Article |
| Zdroj: | JCI Insight. 4 |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.125528 |
| Popis: | Airway neutrophilia occurs in approximately 50% of patients with asthma and is associated with particularly severe disease. Unfortunately, this form of asthma is usually refractory to corticosteroid treatment, and there is an unmet need for new therapies. Pulmonary neutrophilic inflammation is associated with Th17 cells, whose differentiation is controlled by the nuclear receptor retinoic acid–related orphan receptor γt (RORγt). Here, we tested whether VTP-938, a selective inverse agonist of this receptor, can reduce disease parameters in animal models of neutrophilic asthma. When administered before allergic sensitization through the airway, the RORγt inverse agonist blunted allergen-specific Th17 cell development in lung-draining lymph nodes and attenuated allergen-induced production of IL-17. VTP-938 also reduced pulmonary production of IL-17 and airway neutrophilia when given during the allergen challenge of the model. Finally, in an environmentally relevant model of allergic responses to house dust extracts, VTP-938 suppressed production of IL-17 and neutrophilic inflammation and also markedly diminished airway hyperresponsiveness. Together, these findings suggest that orally available inverse agonists of RORγt might provide an effective therapy to treat glucocorticoid-resistant neutrophilic asthma. |
| Databáze: | OpenAIRE |
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