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

ABSTRACT: 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/fl LysMcre). 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.

SUBMITTER: Chung S

PROVIDER: S-EPMC6393185 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Chung Sangwoon S Kim Ji Y JY Song Min-Ae MA Park Gye Y GY Lee Yong G YG Karpurapu Manjula M Englert Joshua A JA Ballinger Megan N MN Pabla Navjot N Chung Hae Y HY Christman John W JW

Allergy 20181105 3

<h4>Background</h4>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 ...[more]

PMID: 30288751

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Project description:Objective: The transcription factor forkhead box protein O1 (FOXO1) is critical for regulating cytokine and chemokine secretion. However, its function in the tumor microenvironment (TME) remains largely unexplored. In this study, we characterized the prognostic value of FOXO1 and the interaction between tumor-derived FOXO1 and M2 macrophages in esophageal squamous cell carcinoma (ESCC). Methods: FOXO1 expression and macrophage infiltration in clinical samples and mouse models were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry staining. Western blotting, qRT-PCR, and enzyme-linked immunosorbent assay were used to evaluate chemokine ligand 20 (CCL20) and colony stimulating factor 1 (CSF-1) expression in FOXO1(+) and FOXO1(-) tumor cells. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and RNA sequencing. Transcriptional activity was measured using chromatin immunoprecipitation (ChIP)-qPCR. Tumor viability was investigated using XTT proliferation and foci formation assays. Results: FOXO1 upregulation in tumor tissues was found to drive the polarization of M0 macrophages and infiltration of M2 macrophages into the TME, resulting in worse prognosis in ESCC patients. CSF-1, a vital factor inducing M0-to-M2 polarization, was upregulated via a FOXO1-mediated mechanism. RNA sequencing results corroborated that the FOXO1-induced macrophages exhibited similar molecular signatures to the IL4-stimulated M2 macrophages. The transwell assays showed that FOXO1 promoted the migration of M2 macrophages via CCL20 secretion, which could be inhibited using an anti-CCL20 antibody. FOXO1(+) tumor-induced M2 macrophages promoted tumor proliferation via the FAK-PI3K-AKT pathway and the PI3K inhibitor could effectively impede the oncogenical process. Conclusions: FOXO1 facilitated M0-to-M2 polarization and the recruitment of M2 macrophages in the TME via the transcriptional modulation of CCL20 and CSF-1. Our data deciphered the FOXO1-dependent mechanism in M2 macrophage infiltration in the TME of ESCC, which has implications for the development of novel prognostic and therapeutic targets to optimize the current treatment against ESCC.

Project description:BACKGROUND:An uncontrolled inflammatory response is a critical pathophysiological feature of sepsis. Mesenchymal stem cells (MSCs) induce macrophage phenotype polarization and reduce inflammation in sepsis. MSC-secreted transforming growth factor beta (TGF-β) participated in the immune modulatory function of MSCs. However, the underlying mechanism of MSC-secreted TGF-β was not fully elucidated in regulation macrophage M2-like polarization. METHODS:The paracrine effects of MSCs on macrophage polarization were studied using a co-culture protocol with LPS-stimulated RAW264.7 cells/mouse peritoneal macrophages and MSCs. The effect of TGF-β in the co-culture system was blocked by the TGF-β receptor inhibitor. To determine the role of MSC-secreted TGF-β, we used recombinant TGF-β to culture with LPS-stimulated RAW264.7 cells. In addition, we employed antibody microarray analysis to determine the mechanisms of MSC secreted TGF-β on LPS-stimulated RAW264.7 cell/mouse peritoneal macrophage M2-like polarization. Furthermore, we used an Akt inhibitor and a FoxO1 inhibitor to inhibit the Akt/FoxO1 pathway. The nuclear translocation of FoxO1 was detected by Western blot. RESULTS:MSCs induced LPS-stimulated RAW264.7 cell/mouse peritoneal macrophage polarization towards the M2-like phenotype and significantly reduced pro-inflammatory cytokine levels via paracrine, which was inhibited by TGF-β receptor inhibitor. Furthermore, we found that MSC-secreted TGF-β enhanced the macrophage phagocytic ability. The antibody microarray analysis and Western blot verified that TGF-β treatment activated the Akt/FoxO1 pathway in LPS-stimulated macrophages, TGF-β-induced FoxO1 nuclear translocation and obviously expressed in the cytoplasm, the effects of TGF-β regulatory effects on LPS-stimulated macrophage were inhibited by pre-treatment with Akt inhibitor and FoxO1 inhibitor. CONCLUSIONS:TGF-β secreted by MSCs could skew LPS-stimulated macrophage polarization towards the M2-like phenotype, reduce inflammatory reactions, and improve the phagocytic ability via the Akt/FoxO1 pathway, providing potential therapeutic strategies for sepsis.

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

Publications

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

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