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.
Highlights
Asthma affects more than 26 million people in the United States [1] and is the most common chronic disease of children and young adults1
Our data indicate that targeted deletion of FoxO1 using either a FoxO1-selective inhibitor AS1842856 or genetic ablation of FoxO1 in macrophages markedly attenuates IRF4 and M2 macrophage-associated gene expression. These findings indicate that FoxO1-IRF4 signaling in alveolar macrophages contributes to the type 2 immune response that results in allergic asthmatic inflammation and that pharmacologic www.impactjournals.com/oncotarget inhibition of FoxO1 could be developed as a novel therapeutic approach for treating refractory asthma through regulation of T helper 2 (TH2)-mediated airway inflammation
There is a growing appreciation that “Alternative Activation” of macrophages drives the “M2 macrophage phenotype” that has tissue reparative, cellular proliferative, and angiogenic mechanisms that could be involved in the pathogenesis of asthma [8, 9, 14, 41,42,43]
Summary
Asthma affects more than 26 million people in the United States [1] and is the most common chronic disease of children and young adults. The pathology of asthma is generally considered to be a type 2 immune reaction that is characterized by eosinophilic airway inflammation that is associated with reversible airflow obstruction and bronchial hyper-reactivity [4, 5]. Growing evidence indicates that inflammatory monocyte and tissue macrophages influence the initiation, progression, and resolution of type 2 immune responses [6, 8,9,10]. Approaches that interrupt the recruitment [9, 11, 12] and/or maintenance [10, 13] of monocyte/macrophages populations in diseased tissues could be developed as novel therapeutic strategies for asthma and a wider range of type 2-driven diseases
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