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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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 3

Age-related transcriptomic changes in TRAMs are not cell autonomous.

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Age-related transcriptomic changes in TRAMs are not cell autonomous. (A)...
(A) Heterochronic adoptive transfer experiments were performed using CD45.1/CD45.2 pairings as indicated (see also Supplemental Figure 3). (B) Representative flow cytometric plots show engraftment of TRAMs from old (18–24 months) (OD) and young adult (4–6 months) (YD) donors into young adult (YR) and old recipients (OR), respectively. Harvesting was performed 60 days after the adoptive transfer. All mice received liposomal clodronate (25 L) intratracheally 72 hours prior to the adoptive transfer (also see Supplemental Figure 3). n = 4 mice per group. (C) Percentage of engraftment of donor alveolar macrophages (AM) 72 hours after intratracheal adoptive transfer of TRAMs from old donors into young adult recipients (OD>YR) or young adult donors into old recipients (YD>OR). n = 4 mice per group. Mann-Whitney U test. (D) Heatmap shows k-means clustering of differentially expressed genes (FDR q < 0.05 in ANOVA-like test) in TRAMs 60 days after heterochronic adoptive transfer into young or old mice. Naive mice did not undergo adoptive transfer. Young and old alveolar macrophages in the same mouse were distinguished by the CD45.1/CD45.2 label (see the full list of genes in Supplemental Table 3). (E) Average z scores for the genes in clusters I, II, and III in D. (F) Heatmap shows k-means clustering of differentially expressed genes (FDR q < 0.05 in ANOVA-list test) in AT2 cells 60 days after heterochronic adoptive transfer of TRAMs (see the full list of genes in Supplemental Table 3). (G) Average z scores for the genes in clusters I, II, and III from F.