Journal of allergy and clinical immunology, 2017-12, Vol.140 (6), p.1550-1561.e8
2017
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- Autor(en) / Beteiligte
- Titel
- Role of C/EBP homologous protein and endoplasmic reticulum stress in asthma exacerbation by regulating the IL-4/signal transducer and activator of transcription 6/transcription factor EC/IL-4 receptor α positive feedback loop in M2 macrophages
- Ist Teil von
- Journal of allergy and clinical immunology, 2017-12, Vol.140 (6), p.1550-1561.e8
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- C/EBP homologous protein (Chop), a marker of endoplasmic reticulum (ER) stress, exhibits aberrant expression patterns during asthma development. However, its exact role in asthma pathogenesis is not fully understood. We aimed to determine the function and mechanism of Chop in the pathogenesis of allergic asthma in patients and animals. Studies were conducted in asthmatic patients and Chop−/− mice to dissect the role of Chop and ER stress in asthma pathogenesis. An ovalbumin (OVA)–induced allergic airway inflammation model was used to address the effect of Chop deficiency on asthma development. Next, the effect of Chop deficiency on macrophage polarization and related signaling pathways was investigated to demonstrate the underlying mechanisms. Asthmatic patients and mice after OVA induction exhibited aberrant Chop expression along with ER stress. Specifically, Chop was noted to be specifically overexpressed in macrophages, and mice deficient in Chop were protected from OVA-induced allergic airway inflammation, as manifested by attenuated airway inflammation, remodeling, and hyperresponsiveness. Chop was found to exacerbate allergic airway inflammation by enhancing M2 programming in macrophages. Mechanistic studies characterized an IL-4/signal transducer and activator of transcription 6/transcription factor EC (Tfec)/IL-4 receptor α positive feedback regulatory loop, in which IL-4 induces Chop expression, which then promotes signal transducer and activator of transcription 6 signaling to transcribe Tfec expression. Finally, Tfec transcribes IL-4 receptor α expression to promote M2 programming in macrophages. Chop and ER stress are implicated in asthma pathogenesis, which involves regulation of M2 programming in macrophages.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0091-6749eISSN: 1097-6825DOI: 10.1016/j.jaci.2017.01.024Titel-ID: cdi_proquest_journals_1973116495
- Format
- –
- Schlagworte
- Adult, Airway management, Allergies, Animals, Asthma, Asthma - immunology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism, C/EBP homologous protein, CCAAT-Enhancer-Binding Proteins - metabolism, CCAAT/enhancer-binding protein, Cell Differentiation, Cells, Cultured, Disease Progression, Endoplasmic reticulum, endoplasmic reticulum stress, Endoplasmic Reticulum Stress - immunology, Feedback, Feedback loops, Feedback, Physiological, Female, Homology, Humans, Inflammation, Interleukin 4, Interleukin-4 - metabolism, Lungs, macrophage, Macrophages, Macrophages - immunology, Male, Mice, Mice, Knockout, Middle Aged, Ovalbumin, Pathogenesis, Phosphorylation, Positive feedback, Proteins, Receptors, Cell Surface - metabolism, Respiratory tract, Respiratory tract diseases, Rodents, Software, STAT6 Transcription Factor - metabolism, Stress, Transcription Factor CHOP - genetics, Transcription Factor CHOP - metabolism, Transcription factors