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Published on: January 6, 2015
Adenovirus-mediated Overexpression of FcγRIIB Attenuates Pulmonary Inflammation and Fibrosis
Zhe Zhang1,2,3,4, Zhujie Cao2, Lin Hou2
1Department of Pulmonary and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, China.
Abstract:
Progressive fibrosing interstitial lung diseases (PF-ILDs) result in high mortality and lack effective therapies. The pathogenesis of PF-ILDs involves macrophages driving inflammation and irreversible fibrosis. Fc-γ receptors (FcγRs) regulate macrophages and inflammation, but their roles in PF-ILDs remain unclear. We characterized the expression of FcγRs and found upregulated FcγRIIB in human and mouse lungs after exposure to silica. FcγRIIB deficiency aggravated lung dysfunction, inflammation, and fibrosis in silica-exposed mice. Using single-cell transcriptomics and in vitro experiments, FcγRIIB was found in alveolar macrophages, where it regulated the expression of fibrosis-related genes Spp1 and Ctss. In mice with macrophage-specific overexpression of FcγRIIB and in mice treated with adenovirus by intratracheal instillation to upregulate FcγRIIB, silica-induced functional and histological changes were ameliorated. Our data from three genetic models and a therapeutic model suggest that FcγRIIB plays a protective role that can be enhanced by adenoviral overexpression, representing a potential therapeutic strategy for PF-ILDs.
Insights
Fc-gamma receptor IIB (FcγRIIB) protects against progressive fibrosing interstitial lung diseases (PF-ILDs). Enhancing FcγRIIB expression in macrophages offers a potential therapeutic strategy for treating PF-ILDs.
Area of Science:
- Immunology
- Pulmonary Medicine
- Cell Biology
Background:
- Progressive fibrosing interstitial lung diseases (PF-ILDs) are characterized by inflammation and irreversible fibrosis, leading to high mortality.
- Macrophages play a critical role in PF-ILD pathogenesis, but the specific mechanisms involving Fc-gamma receptors (FcγRs) are not fully understood.
- Fc-gamma receptors (FcγRs) are key regulators of macrophage function and inflammatory responses.
Purpose of the Study:
- To investigate the role of Fc-gamma receptors (FcγRs) in the pathogenesis of silica-induced progressive fibrosing interstitial lung diseases (PF-ILDs).
- To determine the specific function of Fc-gamma receptor IIB (FcγRIIB) in alveolar macrophages during PF-ILD development.
- To evaluate the therapeutic potential of enhancing FcγRIIB expression for PF-ILDs.
Main Methods:
- Characterization of FcγR expression in human and mouse lungs following silica exposure.
- Assessment of lung dysfunction, inflammation, and fibrosis in FcγRIIB-deficient mice exposed to silica.
- Single-cell transcriptomics and in vitro experiments to elucidate FcγRIIB's regulatory role in alveolar macrophages.
- Evaluation of therapeutic interventions using macrophage-specific FcγRIIB overexpression and adenoviral upregulation in mouse models.
Main Results:
- Fc-gamma receptor IIB (FcγRIIB) expression was upregulated in lungs after silica exposure.
- FcγRIIB deficiency exacerbated silica-induced lung dysfunction, inflammation, and fibrosis.
- FcγRIIB in alveolar macrophages was found to regulate the expression of fibrosis-related genes (Spp1 and Ctss).
- Adenoviral-mediated upregulation of FcγRIIB ameliorated silica-induced lung pathology in mice.
Conclusions:
- Fc-gamma receptor IIB (FcγRIIB) plays a protective role in mitigating lung fibrosis and inflammation in PF-ILD models.
- FcγRIIB expression in macrophages is a critical factor in controlling fibrotic processes.
- Enhancing FcγRIIB expression, particularly via adenoviral delivery, represents a promising therapeutic avenue for PF-ILDs.
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