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The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging
Alexandra C. McQuattie-Pimentel, … , Alexander V. Misharin, G.R. Scott Budinger
Alexandra C. McQuattie-Pimentel, … , Alexander V. Misharin, G.R. Scott Budinger
Published February 15, 2021
Citation Information: J Clin Invest. 2021;131(4):e140299. https://doi.org/10.1172/JCI140299.
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Research Article Aging Immunology Article has an altmetric score of 18

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

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Abstract

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.

Authors

Alexandra C. McQuattie-Pimentel, Ziyou Ren, Nikita Joshi, Satoshi Watanabe, Thomas Stoeger, Monica Chi, Ziyan Lu, Lango Sichizya, Raul Piseaux Aillon, Ching-I Chen, Saul Soberanes, Zhangying Chen, Paul A. Reyfman, James M. Walter, Kishore R. Anekalla, Jennifer M. Davis, Kathryn A. Helmin, Constance E. Runyan, Hiam Abdala-Valencia, Kiwon Nam, Angelo Y. Meliton, Deborah R. Winter, Richard I. Morimoto, Gökhan M. Mutlu, Ankit Bharat, Harris Perlman, Cara J. Gottardi, Karen M. Ridge, Navdeep S. Chandel, Jacob I. Sznajder, William E. Balch, Benjamin D. Singer, Alexander V. Misharin, G.R. Scott Budinger

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Figure 2

Integrated analysis of single-cell RNA-Seq data obtained from the healthy human lung reveals uniform changes in the transcriptome of alveolar macrophages with age.

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Integrated analysis of single-cell RNA-Seq data obtained from the health...
(A) Age distribution in each of the 6 published data sets of single-cell RNA-Seq data obtained from healthy human lungs. (B) Histogram of the age distribution in the combined data from the 6 studies. (C) Schematic of the integrated analysis. Alveolar macrophages were identified by expression of typical macrophage marker genes including FABP4 within each of the individual data sets. After reclustering, clusters composed of contaminating cells identified by reduced expression of FABP4 were eliminated. The resulting integrated analysis showed no clustering of alveolar macrophages as a function of age (see also Supplemental Figure 2). Accordingly, cells from each individual were combined to generate a pseudo-bulk transcriptome, and differentially expressed genes with aging were compared. Full code is available on GitHub (https://github.com/NUPulmonary/Doublehit_Human_scRNA_Analysis; branch – master; commit ID: e486203eb0e1437d73be589a31c803fbc46182bd). (D) Pseudo-bulk analysis of alveolar macrophages from each of the 38 subjects. A heatmap of the differentially expressed genes between individuals under 30 and over 60 years of age was generated. The top columns indicate the chronological age and sex of each subject and the study in which they were included. Down, downregulated; Up, upregulated.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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