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

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

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 8

The response of TRAMs and newly resident MoAMs to a second challenge is similar.

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The response of TRAMs and newly resident MoAMs to a second challenge is ...
(A) Experimental design for the PCA data in D. Mice were intratracheally infected with influenza A virus on day 0 followed by treatment with bleomycin on day 60. (B) Experimental design for the PCA data in E. Mice were administered intratracheal bleomycin on day 0 followed by treatment with a second dose of bleomycin on day 60. (C) Description of cell populations subjected to RNA-Seq. (D) PCA of alveolar macrophage transcriptomes. Colors and symbols refer to panels A and C. (E) PCA of alveolar macrophage transcriptomes. Colors and symbols refer to panels B and C. (F) Volcano plot shows differentially expressed genes (FDR < 0.05) between TRAMs and MoAMs (recruited in response to historic influenza A virus–induced pneumonia as the first injury; black double arrow in A) after the second injury with bleomycin. Representative genes are shown adjacent to the plot (see Supplemental Table 18 for the full list of genes). (G) Volcano plot shows differentially expressed genes (FDR < 0.05) between TRAMs and MoAMs (recruited in response to bleomycin exposure as the first injury; black double arrow in B) after the second injury with bleomycin. Representative genes are shown adjacent to the plot (see Supplemental Table 19 for the full list of genes).