ATP-Binding Cassette Transporter 1 Attenuates Ovalbumin-Induced Neutrophilic Airway Inflammation

Abstract

Apolipoprotein A-I (apoA-I) is an important component of highdensity lipoprotein particles that mediates reverse cholesterol transport out of cells by interacting with the ATP-binding cassette transporter 1 (ABCA1). apoA-I has also been shown to attenuate neutrophilic airway inflammation in experimental ovalbumin (OVA)-induced asthma by reducing the expression of granulocyte colony-stimulating factor (G-CSF). Here, we hypothesized that overexpression of the ABCA1 transporter might similarly attenuate OVA-induced neutrophilic airway inflammation. Tie2-human ABCA1 (hABCA1) mice expressing human ABCA1 under the control of the Tie2 promoter, which is primarily expressed by vascular endothelial cells, but can also be expressed by macrophages, received daily intranasal OVA challenges, 5 d/wk for 5 weeks. OVAchallenged Tie2-hABCA1 mice had significant reductions in total bronchoalveolar lavage fluid (BALF) cells that reflected a decrease in neutrophils, as well as reductions in peribronchial inflammation, OVA-specific IgE levels, and airway epithelial thickness. The reduced airway neutrophilia in OVA-challenged Tie2-hABCA1 mice was associated with significant decreases in G-CSF protein levels in pulmonary vascular endothelial cells, alveolar macrophages, and BALF. Intranasal administration of recombinant murine G-CSF to OVA-challenged Tie2-hABCA1 mice for 5 days increased BALF neutrophils to a level comparable to that of OVA-challenged wildtype mice. We conclude that ABCA1 suppresses OVA-induced airway neutrophilia by reducing G-CSF production by vascular endothelial cells and alveolar macrophages. These findings suggest that ABCA1 expressed by vascular endothelial cells and alveolar macrophages may play important roles in attenuating the severity of neutrophilic airway inflammation in asthma.

Emerging Roles of Apolipoprotein E and Apolipoprotein A-I in the Pathogenesis and Treatment of Lung Disease

“…The increased neutrophilic airway inflammation in OVA-challenged Apoa1-deficient mice was also associated with increases in type 1 (IFN-g) and type 17 (IL-17A) cytokines, but not type 2 cytokines (IL-4, IL-5, and IL-13). Similarly, OVA-challenged mice that overexpressed the human ABCA1 transporter under the Tie2 promoter in pulmonary vascular endothelial cells and macrophages had attenuated increases in BALF neutrophils and G-CSF as compared with wild-type mice (59). Collectively, these studies showed that an apoA-I/ABCA1-dependent pathway inhibited experimental OVA-induced neutrophilic airway inflammation by reducing G-CSF production.…”

The impact of cigarette smoke exposure, and COPD or asthma status on ABC transporter gene expression in human airway epithelial cells

“…To gain insight into ABCA13 biology, we can examine other ABCA family members: Abca1-KO mice have impaired lipid transport resulting in reduced serum cholesterol and HDL, elevated intracellular lipid contents, and abnormal lung structure 41 . In contrast, mice over-expressing human ABCA1 gene showed reduced inflammation and pathology in a model of allergic lung inflammation 42 . In humans and mice, dysfunction of ABCA3 results in surfactant deficiencies and fatal respiratory failure 12,43,44 .…”

The A’s Have It

“…OVA-challenged Tie2-hABCA1 transgenic mice, which conditionally overexpress the human ABCA1 transporter under the Tie2 promoter in vascular endothelial cells and macrophages, have attenuated neutrophilic airway inflammation, airway epithelial wall thickness, and serum levels of OVA-specific IgE. 11 The attenuated neutrophilic airway inflammation in OVA-challenged Tie2-hABCA1 mice was associated with significant reductions in G-CSF protein expression by pulmonary vascular endothelial cells and alveolar macrophages, as well as reduced G-CSF protein levels in BALF. This outcome suggests that ABCA1 expression by vascular endothelial cells and macrophages may reduce allergen-induced neutrophilic airway inflammation by suppressing production of G-CSF.…”

“…ApoA-I and ABCA1 are both expressed by alveolar epithelial cells and alveolar macrophages in the lung, whereas pulmonary vascular endothelial cells and airway smooth muscle cells also express ABCA1. [9][10][11][12][13][14] Mice with a genetic deletion of apoA-I have a phenotype of increased lung inflammation and oxidative stress, as well as enhanced AHR and collagen deposition. 15 In addition, levels of HDL, as well as the antioxidant protein paraoxonase 1, are reduced in Apoa1-deficient mice.…”