The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging
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
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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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 6

The presence of high-molecular-weight hyaluronan reduces proliferation in BMDMs.

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The presence of high-molecular-weight hyaluronan reduces proliferation i...
(A) Schematic of ligand-receptor analysis of AT2 cells and alveolar macrophages during aging. Analysis of differentially expressed genes (FDR < 0.01) in AT2 cells from old (18–24 months) and young adult (4–6 months) mice that were part of a ligand-receptor pair for which the corresponding ligand or receptor was detected in alveolar macrophages identified 72 genes with 255 possible interactions. Thirty-one of these genes encoded matrix proteins, 17 of which were detected in proteomics analysis of BAL fluid from healthy mice, reflecting the composition of the extracellular lining fluid. See Changes in composition of the alveolar lining fluid affect alveolarmacrophage responses to GM-CSF in aging in Results and Supplemental Table 20 for details. (B) Levels of total hyaluronan in BAL fluid from young (4–6 months) and old (18–24 months) mice (n = 10 mice, 5 male and 5 female per age). ***P < 0.0001, by Student’s t test. (C) BMDMs were grown with M-CSF (5 ng/mL) for 4 days, replated, and then stimulated with GM-CSF (5 ng/mL) for 3 days, after which the BMDMs were quantified (n = 6 replicates per experiment). Bar plots show the fold change in cell numbers when cells were treated with GM-CSF on plates coated with matrix from the mouse lung alveolar epithelium–like cell line MLE-12, laminin, and collagen (both 1 μg/cm2) in the presence or absence of high-molecular-weight hyaluronan (1 μg/cm2). Averages and the standard error of 3 independent experiments are shown. *P < 0.05, by 2-way ANOVA followed by Student’s t test.