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 9

The environment determines the response of resident and recruited alveolar macrophages after repeated injury.

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The environment determines the response of resident and recruited alveol...
(A) Schematic for the experimental design for panels B–I. Pairwise comparisons described in panels B–G and in panels G–I are indicated by the double black arrows. (B) Volcano plot shows differentially expressed genes between MoAMs recruited after bleomycin exposure in mice historically treated with bleomycin and mice historically infected with influenza A (FDR < 0.05) (see Supplemental Table 24 for the full list of genes). (C) Volcano plot shows differentially expressed genes between MoAMs recruited after bleomycin exposure in untreated mice and mice historically exposed to bleomycin (FDR q < 0.05). (D) Volcano plot shows differentially expressed genes between MoAMs recruited after bleomycin exposure in untreated mice and mice historically infected with influenza A virus (FDR q < 0.05). (E) Lung compliance was measured in mice after a single bleomycin exposure and 2 sequential bleomycin exposures separated by 60 days. *P < 0.05, 2-way ANOVA followed by unpaired Student’s t test, for comparison between the first and second bleomycin exposures. n = 5 mice per group. (F) Collagen levels were measured in mice after a single bleomycin exposure and 2 sequential bleomycin exposures separated by 60 days. *P < 0.05, 2-way ANOVA followed by an unpaired t test, for comparison between first and second bleomycin exposures. n = 5 mice per group. (G) Volcano plot shows differentially expressed genes in TRAMs after bleomycin exposure in untreated mice and mice historically infected with influenza A virus (FDR < 0.05). (H) Volcano plot shows differentially expressed genes in TRAMs after bleomycin exposure in untreated mice and mice historically exposed to bleomycin (FDR < 0.05). (I) Volcano plot shows differentially expressed genes in TRAMs after bleomycin exposure in mice historically exposed to influenza A virus and mice historically exposed to bleomycin (FDR < 0.05). See also Supplemental Table 23. D, day.