Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois, USA.
Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, USA.
J Clin Invest. 2021 Feb 15;131(4). doi: 10.1172/JCI140299.
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.
肺泡巨噬细胞协调对病毒感染的反应。这些细胞的年龄相关变化可能是老年患者肺炎严重程度不同的基础。我们对单细胞 RNA-Seq 数据进行了综合分析，揭示了人类和小鼠肺泡巨噬细胞转录组中同质的年龄相关变化。通过使用具有连续损伤的遗传谱系追踪、异时性过继转移和联体共生，我们发现肺部微环境导致肺泡巨噬细胞对增殖的年龄相关抵抗，这种抵抗在甲型流感病毒感染期间持续存在。配体-受体对分析将这些变化定位到细胞外基质，其中透明质酸在老年动物中增加，并改变了骨髓来源的巨噬细胞对粒细胞巨噬细胞集落刺激因子 (GM-CSF) 的增殖反应。我们的研究结果表明，靶向衰老肺部微环境的策略对于恢复衰老中肺泡巨噬细胞的功能是必要的。
