FoxO1 is a critical regulator of M2‐like macrophage activation in allergic asthma

• Published in: Allergy (Copenhagen) 2019-03, Vol.74 (3), p.535-548
• Main Authors: Chung, Sangwoon, Kim, Ji Y., Song, Min‐Ae, Park, Gye Y., Lee, Yong G., Karpurapu, Manjula, Englert, Joshua A., Ballinger, Megan N., Pabla, Navjot, Chung, Hae Y., Christman, John W.
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Airway management; airway remodeling; Allergens; Allergens - immunology; Allergic diseases; Allergies; Animals; Asthma; Asthma - diagnosis; Asthma - etiology; Asthma - metabolism; Asthma - therapy; asthmatic inflammation; Bronchial Provocation Tests; Bronchoscopy; Cell activation; Computational fluid dynamics; Disease Models, Animal; Enzyme-linked immunosorbent assay; Exposure; Female; Flow Cytometry; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; FoxO1; FOXO1 protein; Gene expression; Gene Expression Regulation, Neoplastic; Genetic transformation; Humans; Hypersensitivity; Inflammation; Interferon regulatory factor 4; IRF4; Lungs; Macrophage Activation - immunology; Macrophages; Macrophages - immunology; Macrophages - metabolism; Mice; Phenotypes; Respiratory tract diseases; Th2 Cells - immunology; Th2 Cells - metabolism; Therapeutic applications
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/all.13626

Background The pathogenesis of asthma and airway obstruction is the result of an abnormal response to different environmental exposures. The scientific premise of our study was based on the finding that FoxO1 expression is increased in lung macrophages of mice after allergen exposure and human asthmatic patients. Macrophages are capable of switching from one functional phenotype to another, and it is important to understand the mechanisms involved in the transformation of macrophages and how their cellular function affects the peribronchial stromal microenvironment. Methods We employed a murine asthma model, in which mice were treated by intranasal insufflation with allergens for 2‐8 weeks. We used both a pharmacologic approach using a highly specific FoxO1 inhibitor and genetic approaches using FoxO1 knockout mice (FoxO1fl/flLysMcre). Cytokine level in biological fluids was measured by ELISA and the expression of encoding molecules by NanoString assay and qRT‐PCR. Results We show that the levels of FoxO1 gene are significantly elevated in the airway macrophages of patients with mild asthma in response to subsegmental bronchial allergen challenge. Transcription factor FoxO1 regulates a pro‐asthmatic phenotype of lung macrophages that is involved in the development and progression of chronic allergic airway disease. We have shown that inhibition of FoxO1 induced phenotypic conversion of lung macrophages and downregulates pro‐asthmatic and pro‐fibrotic gene expression by macrophages, which contribute to airway inflammation and airway remodeling in allergic asthma. Conclusion Targeting FoxO1 with its downstream regulator IRF4 is a novel therapeutic target for controlling allergic inflammation and potentially reversing fibrotic airway remodeling. Forkhead box protein O1 (FoxO1) gene is significantly elevated in the airway macrophages of patients with mild asthma in response to subsegmental bronchial allergen challenge. Transcription factor FoxO1 regulates a pro‐asthmatic phenotype of lung macrophages that is involved in the development and progression of chronic allergic airway disease. Targeting FoxO1 with its downstream regulator interferon regulatory factor 4 (IRF4) is a novel therapeutic target for controlling allergic inflammation and potentially reversing fibrotic airway remodeling.