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 7

Transcriptional differences between MoAMs and TRAMs persist over the lifespan.

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Transcriptional differences between MoAMs and TRAMs persist over the lif...
(A) Alveolar macrophages from shielded chimeric mice were harvested from mice at the indicated ages, and TRAMs and MoAMs were flow-sorted on the basis of CD45.2 or CD45.1 labeling, respectively. Differentially expressed genes (FDR < 0.01 in an ANOVA-like test) were identified and subjected to k-means clustering. Selected genes and GO processes from each cluster are highlighted (see Supplemental Table 17 for the full list of genes and GO processes). (B) Representative immunofluorescence image of a lung section from a shielded 6-month-old chimeric mouse. Staining for CD45.2 was done to mark TRAMs and for CD45.1 to mark MoAMs. A combined image overlaid on a phase-contrast image is shown. Scale bars: 40 μm and 10 μm (enlarged inset). (C) Venn diagram shows overlap of differentially expressed genes between MoAMs and TRAMs in this model (clusters IV and V in A) with an independent data set from Misharin et al. (8) collected 10 months after bleomycin exposure. (D) Reduced representation bisulfite sequencing was performed on TRAMs and MoAMs from 6-month-old mice. The frequency of methylated CpG motifs in promoter regions within 1000 bp upstream and downstream of the transcriptional start site (TSS) of differentially expressed genes between TRAMs and MoAMs in shielded chimeric mice was compared with their frequency across the genome. A similar analysis was performed using putative enhancer regions specific to alveolar macrophages defined as consensus H3K4me1 peaks by Lavin et al. (7). No significant differences in DNA methylation were detected.