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Isolation and In Vitro Culture of Murine and Human Alveolar Macrophages
Published on: April 20, 2018
Macrophage PPAR-γ suppresses long-term lung fibrotic sequelae following acute influenza infection
Su Huang1, Nick P Goplen1, Bibo Zhu1
1Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Rochester, Minnesota, United States of America.
Abstract:
Influenza virus causes a heterogeneous respiratory infectious disease ranging from self-limiting symptoms to non-resolving pathology in the lungs. Worldwide, seasonal influenza infections claim ~500,000 lives annually. Recent reports describe pathologic pulmonary sequelae that result in remodeling the architecture of lung parenchyma following respiratory infections. These dysfunctional recovery processes that disproportionately impact the elderly have been understudied. Macrophages are involved in tissue remodeling and are critical for survival of severe influenza infection. Here, we found intrinsic deficiency of the nuclear receptor PPAR-γ in myeloid cells delayed the resolution of pulmonary inflammation following influenza infection. Mice with myeloid cell-specific PPAR-γ deficiency subsequently presented with increased influenza-induced deposition of pulmonary collagen compared to control mice. This dysfunctional lung remodeling was progressive and sustained for at least 3 months following infection of mice with myeloid PPAR-γ deficiency. These progressive changes were accompanied by a pro-fibrotic gene signature from lung macrophages and preceded by deficiencies in activation of genes involved with damage repair. Importantly similar aberrant gene expression patterns were also found in a secondary analysis of a study where macrophages were isolated from patients with fibrotic interstitial lung disease. Quite unexpectedly, mice with PPAR-γ deficient macrophages were more resistant to bleomycin-induced weight loss whereas extracellular matrix deposition was unaffected compared to controls. Therefore PPAR-γ expression in macrophages may be a pathogen-specific limiter of organ recovery rather than a ubiquitous effector pathway in response to generic damage.
Insights
Nuclear receptor PPAR-γ deficiency in myeloid cells impairs lung repair after influenza infection, leading to sustained inflammation and fibrosis. This suggests PPAR-γ is crucial for resolving lung damage, particularly in elderly populations.
Area of Science:
- Immunology
- Pulmonary Medicine
- Molecular Biology
Background:
- Influenza virus causes severe respiratory illness with significant mortality.
- Pulmonary sequelae, including lung remodeling, can occur after respiratory infections, disproportionately affecting the elderly.
- Macrophages play a key role in tissue repair and response to influenza.
Purpose of the Study:
- To investigate the role of Peroxisome proliferator-activated receptor gamma (PPAR-γ) in myeloid cells during influenza-induced lung inflammation and repair.
- To determine if PPAR-γ deficiency in macrophages affects lung remodeling and fibrosis post-influenza.
Main Methods:
- Utilized a mouse model with myeloid cell-specific PPAR-γ deficiency.
- Infected mice with influenza virus and assessed pulmonary inflammation, collagen deposition, and gene expression in lung macrophages.
- Analyzed lung tissue for extracellular matrix deposition and changes in gene expression.
- Compared responses to bleomycin-induced lung injury in PPAR-γ deficient mice.
Main Results:
- Myeloid cell-specific PPAR-γ deficiency delayed the resolution of pulmonary inflammation following influenza infection.
- These mice exhibited increased and sustained collagen deposition, indicating dysfunctional lung remodeling.
- Lung macrophages showed a pro-fibrotic gene signature, with impaired activation of damage repair genes.
- PPAR-γ deficient macrophages conferred resistance to bleomycin-induced weight loss without affecting extracellular matrix deposition.
Conclusions:
- Intrinsic PPAR-γ deficiency in myeloid cells impairs lung recovery after influenza infection, leading to progressive fibrosis.
- PPAR-γ in macrophages appears to be a pathogen-specific regulator of organ recovery, not a universal damage response pathway.
- These findings highlight a potential therapeutic target for managing post-influenza lung complications, especially in vulnerable populations.
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