The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging
Open accessAbstract
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.
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The pathogenic role of Mo-AMs in lung fibrosis is largely attributed to their production of pro-fibrotic mediators such as TGF-β, PDGF-α, osteopontin, and MMPs.
“The pathogenic role of Mo-AMs in lung fibrosis has been largely attributed to their activity in producing a number of pro-fibrotic mediators, such as TGF-β, PDGF-α, osteopontin (OPN), and MMPs1,3,11,13,15,18,28.”
From TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity (2025) · cites this paper as [15]
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- Authors
- McQuattie-Pimentel, A. C., Ren, Z., Joshi, N., Watanabe, S., Stoeger, T., Chi, M., Lu, Z., Sichizya, L., Aillon, R. P., Chen, C.-I., Soberanes, S., Chen, Z., Reyfman, P. A., Walter, J. M., Anekalla, K. R., Davis, J. M., Helmin, K. A., Runyan, C. E., Abdala-Valencia, H., Nam, K., Meliton, A. Y., Winter, D. R., Morimoto, R. I., Mutlu, G. M., Bharat, A., Perlman, H., Gottardi, C. J., Ridge, K. M., Chandel, N. S., Sznajder, J. I., Balch, W. E., Singer, B. D., Misharin, A. V., & Budinger, G. R. S.
- Affiliations
- Northwestern University (US)
- University of Chicago Medical Center (US)
- Scripps Research Institute (US)
- ORCID
- Ren, Ziyou
- Joshi, Nikita
- Watanabe, Satoshi
- Stoeger, Thomas
- Lu, Ziyan
- Sichizya, Lango
- Chen, Ching-I
- Soberanes, Saul
- Chen, Zhangying
- Reyfman, Paul A.
- Walter, James M.
- Anekalla, Kishore R.
- Helmin, Kathryn A.
- Runyan, Constance E.
- Abdala-Valencia, Hiam
- 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
- Venue
- Journal of Clinical Investigation
- Published
- 2021-02-15
- Volume
- 131
- Issue
- 4
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC7919859
- OpenAlex
- W3133294399
- Cited by
- 177
- References
- 56
- Citations by year
- 2026: 30 · 2025: 35 · 2024: 31 · 2023: 30 · 2022: 34 · 2021: 17
- FWCI
- 10.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH (AG490665, HL135124,AG049665,AI135964, HL071643,HL14575)
- Veterans Administration (CX01777)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- alveolar macrophages, lung aging, lung microenvironment, extracellular matrix, hyaluronic acid, macrophage proliferation, influenza A virus infection, GM-CSF signaling, bone marrow-derived macrophages, lineage tracing, parabiosis, single-cell transcriptomics
- MeSH terms
- RNA-Seq, Aging, Animals, Humans, Lung, Mice, Transgenic, Macrophages, Alveolar, Mice, Cellular Microenvironment
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