Macrophage PPAR-γ suppresses long-term lung fibrotic sequelae following acute influenza infection

Autoři: Su Huang aff001;  Nick P. Goplen aff001;  Bibo Zhu aff001;  In Su Cheon aff001;  Youngmin Son aff001;  Zheng Wang aff001;  Chaofan Li aff001;  Qigang Dai aff001;  Li Jiang aff001;  Min Xiang aff001;  Eva M. Carmona aff001;  Robert Vassallo aff001;  Andrew H. Limper aff001;  Jie Sun aff001
Působiště autorů: Thoracic 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 aff001;  Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Rochester, Minnesota, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


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.

Klíčová slova:

Alveolar macrophages – Collagens – Gene expression – Influenza – Influenza viruses – Macrophages – Pulmonary fibrosis – Respiratory infections


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