Oncotarget

Research Papers: Immunology:

FoxO1 regulates allergic asthmatic inflammation through regulating polarization of the macrophage inflammatory phenotype

Sangwoon Chung, Tae Jin Lee, Brenda F. Reader, Ji Young Kim, Yong Gyu Lee, Gye Young Park, Manjula Karpurapu, Megan N. Ballinger, Feng Qian, Luiza Rusu, Hae Young Chung, Terry G. Unterman, Carlo M. Croce, John W. Christman _

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Oncotarget. 2016; 7:17532-17546. https://doi.org/10.18632/oncotarget.8162

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Abstract

Sangwoon Chung1, Tae Jin Lee2, Brenda F. Reader1, Ji Young Kim1, Yong Gyu Lee1, Gye Young Park3, Manjula Karpurapu1, Megan N. Ballinger1, Feng Qian1, Luiza Rusu1, Hae Young Chung4, Terry G. Unterman5, Carlo M. Croce2 and John W. Christman1

1 Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio, USA

2 Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA

3 Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

4 Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea

5 Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA

Correspondence to:

John W. Christman, email:

Carlo M. Croce, email:

Keywords: FoxO1, asthma, eosinophilic lung inflammation, M2 macrophage phenotype, Immunology and Microbiology Section, Immune response, Immunity

Received: February 02, 2016 Accepted: March 01, 2016 Published: March 17, 2016

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.


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