The Lung Microenvironment Shapes a Dysfunctional Response of Alveolar Macrophages in Aging

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2021 Feb 15

PMID 33586677

Citations 76

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

Gokhan 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

Affiliations

Soon will be listed here.

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.

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