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 Andrew 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

doi:10.1172/JCI140299

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 Andrew Reyfman, James M. Walter, Kishore R. Anekalla, Jennifer M. Davis, Kathryn A. Helmin, Constance E. Runyan, Hiam Abdala-Valencia, Kiwon NamAngelo 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

104 Scopus citations

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.

Original language	English (US)
Article number	e140299
Journal	Journal of Clinical Investigation
Volume	131
Issue number	4
DOIs	https://doi.org/10.1172/JCI140299
State	Published - Feb 15 2021

Funding

The Northwestern University Flow Cytometry Core Facility is supported by a National Cancer Institute (NCI) Cancer Center Support Grant (P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center). Cell sorting was performed on a BD FACSAria SORP cell sorter purchased through the support of NIH grant 1S10OD011996-01. This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and the Feinberg School of Medicine's Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. GRSB is supported by the NIH (U19AI135964, P01AG049665, R01HL147575, P01HL071643, and R01HL154686) and the Department of Veterans Affairs (I01CX001777). BDS is supported by the NIH (K08HL128867, U19AI135964, R01HL149883, and P01AG049665). PAR is supported by the NIH (K08HL146943) and by an ATS Foundation/ Boehringer Ingelheim Partner Award for research in idiopathic pulmonary fibrosis. AVM is supported by the NIH (U19AI135964, P01AG049665, R56HL135124, and R01HL153312). AB is supported by the NIH (HL145478, HL147290, and HL147575). JIS is supported by the NIH (R01HL154686, P01AG049665, and P01HL071643). RGW is supported by the NIH (U19AI135964) and a GlaxoSmithKline Distinguished Scholar in Respiratory Health grant from the CHEST Foundation. NSC is supported by the NIH (P01AG049665 and P01HL071643). DRW is supported by funding from the Arthritis National Research Foundation (ANRF), the American Heart Association (AHA), the Scleroderma Foundation, the American Lung Association (ALA), the American Thoracic Society (ATS), the American Federation for Aging (AFAR), and the NIH (U19AI135964). SW is supported by the MSD Life Science Foundation, the Public Interest Incorporated Foundation, Japan, and by a David W. Cugell and Christina Enroth-Cugell Fellowship. KMR is supported by the NIH (P01AG049665 and P01HL071643). CJG is supported by the NIH (R01AR073270 and R01HL134800). GMM is supported by the NIH (R01ES015024, U01ES026718, and P30ES027792). TS is supported by the NIH (K99AG068544) and the National Science Foundation (NSF) (1956338). ZR is supported by the AHA (20POST35180141).

ASJC Scopus subject areas

General Medicine

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10.1172/JCI140299

Cite this

McQuattie-Pimentel, A. C., Ren, Z., Joshi, N., Watanabe, S., Stoeger, T., Chi, M., Lu, Z., Sichizya, L., Aillon, R. P., Chen, C. I., Soberanes, S., Chen, Z., Reyfman, P. A., Walter, J. M., Anekalla, K. R., Davis, J. M., Helmin, K. A., Runyan, C. E., Abdala-Valencia, H., ... Budinger, G. R. S. (2021). The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging. Journal of Clinical Investigation, 131(4), Article e140299. https://doi.org/10.1172/JCI140299

@article{acba939dfc324537913acc6e901c8b61,

title = "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.",

author = "McQuattie-Pimentel, {Alexandra C.} and Ziyou Ren and Nikita Joshi and Satoshi Watanabe and Thomas Stoeger and Monica Chi and Ziyan Lu and Lango Sichizya and Aillon, {Raul Piseaux} and Chen, {Ching I.} and Saul Soberanes and Zhangying Chen and Reyfman, {Paul Andrew} and Walter, {James M.} and Anekalla, {Kishore R.} and Davis, {Jennifer M.} and Helmin, {Kathryn A.} and Runyan, {Constance E.} and Hiam Abdala-Valencia and Kiwon Nam and Meliton, {Angelo Y.} and Winter, {Deborah R.} and Morimoto, {Richard I.} and Mutlu, {G{\"o}khan M.} and Ankit Bharat and Harris Perlman and Gottardi, {Cara J.} and Ridge, {Karen M.} and Chandel, {Navdeep S.} and Sznajder, {Jacob I.} and Balch, {William E.} and Singer, {Benjamin D.} and Misharin, {Alexander V.} and Budinger, {G. R.Scott}",

note = "Funding Information: The Northwestern University Flow Cytometry Core Facility is supported by a National Cancer Institute (NCI) Cancer Center Support Grant (P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center). Cell sorting was performed on a BD FACSAria SORP cell sorter purchased through the support of NIH grant 1S10OD011996-01. This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and the Feinberg School of Medicine's Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. GRSB is supported by the NIH (U19AI135964, P01AG049665, R01HL147575, P01HL071643, and R01HL154686) and the Department of Veterans Affairs (I01CX001777). BDS is supported by the NIH (K08HL128867, U19AI135964, R01HL149883, and P01AG049665). PAR is supported by the NIH (K08HL146943) and by an ATS Foundation/ Boehringer Ingelheim Partner Award for research in idiopathic pulmonary fibrosis. AVM is supported by the NIH (U19AI135964, P01AG049665, R56HL135124, and R01HL153312). AB is supported by the NIH (HL145478, HL147290, and HL147575). JIS is supported by the NIH (R01HL154686, P01AG049665, and P01HL071643). RGW is supported by the NIH (U19AI135964) and a GlaxoSmithKline Distinguished Scholar in Respiratory Health grant from the CHEST Foundation. NSC is supported by the NIH (P01AG049665 and P01HL071643). DRW is supported by funding from the Arthritis National Research Foundation (ANRF), the American Heart Association (AHA), the Scleroderma Foundation, the American Lung Association (ALA), the American Thoracic Society (ATS), the American Federation for Aging (AFAR), and the NIH (U19AI135964). SW is supported by the MSD Life Science Foundation, the Public Interest Incorporated Foundation, Japan, and by a David W. Cugell and Christina Enroth-Cugell Fellowship. KMR is supported by the NIH (P01AG049665 and P01HL071643). CJG is supported by the NIH (R01AR073270 and R01HL134800). GMM is supported by the NIH (R01ES015024, U01ES026718, and P30ES027792). TS is supported by the NIH (K99AG068544) and the National Science Foundation (NSF) (1956338). ZR is supported by the AHA (20POST35180141). Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",

year = "2021",

month = feb,

day = "15",

doi = "10.1172/JCI140299",

language = "English (US)",

volume = "131",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "4",

}

McQuattie-Pimentel, AC, Ren, Z, Joshi, N, Watanabe, S, Stoeger, T, Chi, M, Lu, Z, Sichizya, L, Aillon, RP, Chen, CI, Soberanes, S, Chen, Z, Reyfman, PA, Walter, JM, Anekalla, KR, Davis, JM, Helmin, KA, Runyan, CE, Abdala-Valencia, H, Nam, K, Meliton, AY, Winter, DR , Morimoto, RI, Mutlu, GM, Bharat, A , Perlman, H , Gottardi, CJ , Ridge, KM , Chandel, NS , Sznajder, JI, Balch, WE, Singer, BD , Misharin, AV & Budinger, GRS 2021, 'The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging', Journal of Clinical Investigation, vol. 131, no. 4, e140299. https://doi.org/10.1172/JCI140299

TY - JOUR

T1 - The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging

AU - McQuattie-Pimentel, Alexandra C.

AU - Ren, Ziyou

AU - Joshi, Nikita

AU - Watanabe, Satoshi

AU - Stoeger, Thomas

AU - Chi, Monica

AU - Lu, Ziyan

AU - Sichizya, Lango

AU - Aillon, Raul Piseaux

AU - Chen, Ching I.

AU - Soberanes, Saul

AU - Chen, Zhangying

AU - Reyfman, Paul Andrew

AU - Walter, James M.

AU - Anekalla, Kishore R.

AU - Davis, Jennifer M.

AU - Helmin, Kathryn A.

AU - Runyan, Constance E.

AU - Abdala-Valencia, Hiam

AU - Nam, Kiwon

AU - Meliton, Angelo Y.

AU - Winter, Deborah R.

AU - Morimoto, Richard I.

AU - Mutlu, Gökhan M.

AU - Bharat, Ankit

AU - Perlman, Harris

AU - Gottardi, Cara J.

AU - Ridge, Karen M.

AU - Chandel, Navdeep S.

AU - Sznajder, Jacob I.

AU - Balch, William E.

AU - Singer, Benjamin D.

AU - Misharin, Alexander V.

AU - Budinger, G. R.Scott

N1 - Funding Information: The Northwestern University Flow Cytometry Core Facility is supported by a National Cancer Institute (NCI) Cancer Center Support Grant (P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center). Cell sorting was performed on a BD FACSAria SORP cell sorter purchased through the support of NIH grant 1S10OD011996-01. This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and the Feinberg School of Medicine's Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. GRSB is supported by the NIH (U19AI135964, P01AG049665, R01HL147575, P01HL071643, and R01HL154686) and the Department of Veterans Affairs (I01CX001777). BDS is supported by the NIH (K08HL128867, U19AI135964, R01HL149883, and P01AG049665). PAR is supported by the NIH (K08HL146943) and by an ATS Foundation/ Boehringer Ingelheim Partner Award for research in idiopathic pulmonary fibrosis. AVM is supported by the NIH (U19AI135964, P01AG049665, R56HL135124, and R01HL153312). AB is supported by the NIH (HL145478, HL147290, and HL147575). JIS is supported by the NIH (R01HL154686, P01AG049665, and P01HL071643). RGW is supported by the NIH (U19AI135964) and a GlaxoSmithKline Distinguished Scholar in Respiratory Health grant from the CHEST Foundation. NSC is supported by the NIH (P01AG049665 and P01HL071643). DRW is supported by funding from the Arthritis National Research Foundation (ANRF), the American Heart Association (AHA), the Scleroderma Foundation, the American Lung Association (ALA), the American Thoracic Society (ATS), the American Federation for Aging (AFAR), and the NIH (U19AI135964). SW is supported by the MSD Life Science Foundation, the Public Interest Incorporated Foundation, Japan, and by a David W. Cugell and Christina Enroth-Cugell Fellowship. KMR is supported by the NIH (P01AG049665 and P01HL071643). CJG is supported by the NIH (R01AR073270 and R01HL134800). GMM is supported by the NIH (R01ES015024, U01ES026718, and P30ES027792). TS is supported by the NIH (K99AG068544) and the National Science Foundation (NSF) (1956338). ZR is supported by the AHA (20POST35180141). Publisher Copyright: © 2021, American Society for Clinical Investigation.

PY - 2021/2/15

Y1 - 2021/2/15

N2 - 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.

AB - 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.

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U2 - 10.1172/JCI140299

DO - 10.1172/JCI140299

M3 - Article

C2 - 33586677

AN - SCOPUS:85101460569

SN - 0021-9738

VL - 131

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 4

M1 - e140299

ER -

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

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