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 5

The aging microenvironment confers resistance to GM-CSF signaling in alveolar macrophages.

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The aging microenvironment confers resistance to GM-CSF signaling in alv...
(A) Schematic of the experimental design for B. Green represents young adult (4–6 months) mice, and gray represents old (18–24 months) mice. (B) Survival curve for young adult (4 months) or old (18 months) mice intratracheally infected with influenza A virus (A/WSN/33), 25 PFU/animal, with or without intratracheal GM-CSF (5 mg/kg). n = 5 per group. Mantel-Cox log-rank test. (C) Box-and-whisker plot shows the expression of genes known to regulate signaling through the GM-CSF receptor (Csf2ra, Csf2rb) and the M-CSF receptor (Csf1r) in TRAMs from young and old naive mice (n = 3–4 mice per group). FDR > 0.05 after multipair t test adjustment. (D) Box-and-whisker plot showing expression of Csf1, Csf2, and Il34 in AT2 cells from young and old naive mice (n = 4 mice per group). FDR > 0.05 after multipair t test adjustment. (E) Schematic for F–H. Young adult (4 months) and old (18 months) mice were treated with intratracheal GM-CSF (5 mg/kg), and alveolar macrophages were harvested 14 days later (see also Supplemental Figure 5C). (F) Heatmap shows k-means clustering of cell-cycle genes between TRAMs from GM-CSF–treated and untreated young adult and old mice. Representative genes and GO processes are shown (see also Supplemental Table 13). (G) Volcano plot shows differentially expressed genes in young mice (FDR q < 0.05) after treatment with intratracheal GM-CSF (see also Supplemental Table 14). (H) Volcano plot shows differentially expressed genes in old mice (FDR q < 0.05) after treatment with intratracheal GM-CSF (see also Supplemental Table 14). CPM, counts per million reads.