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

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.

Automated summary

This study identified homogeneous age-related changes in the transcriptome of alveolar macrophages and demonstrated that the lung microenvironment affects the proliferation capacity of these cells, which in turn impacts the resistance of older patients to influenza viral infection. Targeting strategies towards the aging lung microenvironment may be necessary to restore alveolar macrophage function in aging individuals.