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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.

SUBMITTER: McQuattie-Pimentel AC

PROVIDER: S-EPMC7919859 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

McQuattie-Pimentel Alexandra C AC Ren Ziyou Z Joshi Nikita N Watanabe Satoshi S Stoeger Thomas T Chi Monica M Lu Ziyan Z Sichizya Lango L Aillon Raul Piseaux RP Chen Ching-I CI Soberanes Saul S Chen Zhangying Z Reyfman Paul A PA Walter James M JM Anekalla Kishore R KR Davis Jennifer M JM Helmin Kathryn A KA Runyan Constance E CE Abdala-Valencia Hiam H Nam Kiwon K Meliton Angelo Y AY Winter Deborah R DR Morimoto Richard I RI Mutlu Gökhan M GM Bharat Ankit A Perlman Harris H Gottardi Cara J CJ Ridge Karen M KM Chandel Navdeep S NS Sznajder Jacob I JI Balch William E WE Singer Benjamin D BD Misharin Alexander V AV Budinger G R Scott GRS

The Journal of clinical investigation 20210201 4

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-r ...[more]

PMID: 33586677

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Project description:IntroductionAlveolar macrophages (AMs) are critical in the development of lung adenocarcinoma driven by epidermal growth factor receptor (EGFR) mutations. Whether interstitial macrophages (IMs) are also involved in lung tumorigenesis is still unclear. Thus, the aim of this study is to evaluate the role of both AM and IM in the development of EGFR mutant driven lung adenocarcinoma.MethodsWe used the EGFR mutant doxycycline-inducible mouse model of lung adenocarcinoma to deplete interstitial or AMs by clodronate-encapsulated liposomes administered intravenously (IV) and intratracheally (IT), respectively. Tumor burden, AMs, and the tumor microenvironment were examined by immunohistochemistry, bronchoalveolar lavage fluid or flow cytometry.ResultsClodronate treatment resulted in a significant reduction of tumor burden compared with vehicle liposomes alone. Elimination of AMs resulted in a significant reduction of proliferation compared with IV treatment. However, both treatments resulted in a significantly higher number of Ki67 positive cells compared with control mice, suggesting that tumor cells still proliferate despite the treatment. The number of natural killer cells decreased during tumor development, and it remained low even after the elimination of AMs. We also observed that IT instillation of clodronate significantly increased the number of CD8+ T cells, which was higher compared with vehicle-treated mice and mice where only IMs were depleted. The similar trend was observed in immunohistological analyses of CD8+ T cells.ConclusionsThese results suggest that the reduction of AMs has a stronger impact on restricting tumor progression compared with targeting IMs. The depletion of AMs leads to an elevated infiltration of CD8+ T cells into the lung that might be responsible for tumor growth impairment. Altogether, elimination of AMs is a better strategy to reduce EGFR mutant tumor growth and is less toxic, suggesting the selectively targeting of AMs to complement established therapies.

Dataset Information

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

Publications

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

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