The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging

Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar ma...

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Bibliographic Details
Published in:The Journal of clinical investigation 2021-02, Vol.131 (4), p.1-20
Main Authors: McQuattie-Pimentel, Alexandra C, Ren, Ziyou, Joshi, Nikita, Watanabe, Satoshi, Stoeger, Thomas, Chi, Monica, Lu, Ziyan, Sichizya, Lango, Aillon, Raul Piseaux, Chen, Ching-I, Soberanes, Saul, Chen, Zhangying, Reyfman, Paul A, Walter, James M, Anekalla, Kishore R, Davis, Jennifer M, Helmin, Kathryn A, Runyan, Constance E, Abdala-Valencia, Hiam, Nam, Kiwon, Meliton, Angelo Y, Winter, Deborah R, Morimoto, Richard I, Mutlu, Gökhan M, Bharat, Ankit, Perlman, Harris, Gottardi, Cara J, Ridge, Karen M, Chandel, Navdeep S, Sznajder, Jacob I, Balch, William E, Singer, Benjamin D, Misharin, Alexander V, Budinger, G R Scott
Format: Article
Language:English
Subjects:
Adoptive transfer
Age
Age factors in disease
Aging
Aging - immunology
Aging - pathology
Animals
Biomedical research
Bone marrow
Cell adhesion & migration
Cell cycle
Cellular Microenvironment - immunology
Colony-stimulating factor
Coronaviruses
COVID-19
DNA methylation
Extracellular matrix
Gene expression
Genetic aspects
Granulocyte-macrophage colony-stimulating factor
Granulocytes
Health aspects
Humans
Hyaluronic acid
Hypotheses
Influenza
Influenza A
Ligands
Lung - immunology
Lung - pathology
Lung diseases
Macrophages
Macrophages, Alveolar - immunology
Macrophages, Alveolar - pathology
Mice
Mice, Transgenic
Microenvironments
Older people
Parabiosis
Pneumonia
Population
Recovery of function
Risk factors
RNA-Seq
Transcriptomes
Viral infections
Young adults
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Summary:Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI140299