title: FoxO1 regulates allergic asthmatic inflammation through regulating polarization of the macrophage inflammatory phenotype.
abstract: Inflammatory monocyte and tissue macrophages influence the initiation, progression, and resolution of type 2 immune responses, and alveolar macrophages are the most prevalent immune-effector cells in the lung. While we were characterizing the M1- or M2-like macrophages in type 2 allergic inflammation, we discovered that FoxO1 is highly expressed in alternatively activated macrophages. Although several studies have been focused on the fundamental role of FoxOs in hematopoietic and immune cells, the exact role that FoxO1 plays in allergic asthmatic inflammation in activated macrophages has not been investigated. Growing evidences indicate that FoxO1 acts as an upstream regulator of IRF4 and could have a role in a specific inflammatory phenotype of macrophages. Therefore, we hypothesized that IRF4 expression regulated by FoxO1 in alveolar macrophages is required for established type 2 immune mediates allergic lung inflammation. Our data indicate that targeted deletion of FoxO1 using FoxO1-selective inhibitor AS1842856 and genetic ablation of FoxO1 in macrophages significantly decreases IRF4 and various M2 macrophage-associated genes, suggesting a mechanism that involves FoxO1-IRF4 signaling in alveolar macrophages that works to polarize macrophages toward established type 2 immune responses. In response to the challenge of DRA (dust mite, ragweed, and Aspergillus) allergens, macrophage specific FoxO1 overexpression is associated with an accentuation of asthmatic lung inflammation, whereas pharmacologic inhibition of FoxO1 by AS1842856 attenuates the development of asthmatic lung inflammation. Thus, our study identifies a role for FoxO1-IRF4 signaling in the development of alternatively activated alveolar macrophages that contribute to type 2 allergic airway inflammation.
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: Sangwoon
authors.initials: S
authors.lastname: Chung
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Lee
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Reader
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: Yong Gyu
authors.initials: YG
authors.lastname: Lee
authors.affiliation: Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Gye Young
authors.initials: GY
authors.lastname: Park
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Karpurapu
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Ballinger
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: Luiza
authors.initials: L
authors.lastname: Rusu
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
authors.affiliation: Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA.
authors.forename: Terry G
authors.initials: TG
authors.lastname: Unterman
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology*; D016764:Cell Polarity / Q000276:immunology; D000071161:Forkhead Box Protein O1 / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D000099218:Interferon Regulatory Factor-4
chemical_list: D000071161:Forkhead Box Protein O1; D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4; C467200:Foxo1 protein, mouse
keywords: FoxO1; Immune response; Immunity; Immunology and Microbiology Section; M2 macrophage phenotype; asthma; eosinophilic lung inflammation