Targeted Disruption of Ig-Hepta/Gpr116 Causes Emphysema-like Symptoms That Are Associated with Alveolar Macrophage Activation

Donna Maretta Ariestanti,Hikaru Ando,Shigehisa Hirose,Nobuhiro Nakamura

doi:10.1074/jbc.m115.648311

Donna Maretta Ariestanti, Hikaru Ando + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m115.648311

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Abstract

Ig-Hepta/GPR116 is a member of the G protein-coupled receptor family predominantly expressed in the alveolar type II epithelial cells of the lung. Previous studies have shown that Ig-Hepta is essential for lung surfactant homeostasis, and loss of its function results in high accumulation of surfactant lipids and proteins in the alveolar space. Ig-Hepta knock-out (Ig-Hepta(-/-)) mice also exhibit emphysema-like symptoms, including accumulation of foamy alveolar macrophages (AMs), but its pathogenic mechanism is unknown. Here, we show that the bronchoalveolar lavage fluid obtained from Ig-Hepta(-/-) mice contains high levels of inflammatory mediators, lipid hydroperoxides, and matrix metalloproteinases (MMPs), which are produced by AMs. Accumulation of reactive oxygen species was observed in the AMs of Ig-Hepta(-/-) mice in an age-dependent manner. In addition, nuclear factor-κB (NF-κB) is activated and translocated into the nuclei of the AMs of Ig-Hepta(-/-) mice. Release of MMP-2 and MMP-9 from the AMs was strongly inhibited by treatment with inhibitors of oxidants and NF-κB. We also found that the level of monocyte chemotactic protein-1 is increased in the embryonic lungs of Ig-Hepta(-/-) mice at 18.5 days postcoitum, when AMs are not accumulated and activated. These results suggest that Ig-Hepta plays an important role in regulating macrophage immune responses, and its deficiency leads to local inflammation in the lung, where AMs produce excessive amounts of reactive oxygen species and up-regulate MMPs through the NF-κB signaling pathway.

Highlights

Ig-Hepta knock-out mice exhibit emphysema-like symptoms, but their pathogenesis remains unclear
Because alveolar macrophages (AMs) have been shown to play a pivotal role in the pathogenesis of emphysema, we determined and compared reactive oxygen species (ROS) accumulation, nuclear factor-␬B (NF-␬B) activation, and matrix metalloproteinases (MMPs) production in the AMs of wild-type and Ig-HeptaϪ/Ϫ mice
Our results showed that the AMs of Ig-HeptaϪ/Ϫ mice have response profiles similar to those observed in emphysema

Summary

Background

Ig-Hepta knock-out mice exhibit emphysema-like symptoms, but their pathogenesis remains unclear. We found that the level of monocyte chemotactic protein-1 is increased in the embryonic lungs of Ig-Hepta؊/؊ mice at 18.5 days postcoitum, when AMs are not accumulated and activated These results suggest that Ig-Hepta plays an important role in regulating macrophage immune responses, and its deficiency leads to local inflammation in the lung, where AMs produce excessive amounts of reactive oxygen species and up-regulate MMPs through the NF-␬B signaling pathway. Mice deficient in Ig-Hepta exhibit massive accumulation of pulmonary surfactant in the alveoli due to abnormal synthesis and catabolism of surfactant lipids and proteins in the alveolar type II cells [27,28,29]. Excess amounts of ROS induce the secretion of MMP-2 and MMP-9 from AMs through activation of NF-␬B These observations suggest that Ig-Hepta plays an important role in lung homeostasis by regulating immune regulation in the alveoli

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DISCUSSION