Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
J Leukoc Biol. 2022 Dec;112(6):1371-1386. doi: 10.1002/JLB.3HI0620-399RR. Epub 2022 Sep 19.
Alveolar macrophages (AMs) are tissue-resident cells of the lower airways that perform many homeostatic functions critical for pulmonary health and protection against pathogens. However, little is known about the factors that shape AMs during healthy aging. In these studies, we sought to characterize age-related changes in AM phenotype, function, and responses to a physiologic stressor, that is, distal injury. Age was associated with a wide range of changes in cell surface receptor and gene expression by AMs, reflecting a unique alternatively activated phenotype. AMs from aged mice also exhibited markers of cellular senescence along with down-regulation of genes involved in growth and cell cycle pathways relative to young controls. Furthermore, AMs from aged mice showed a stunted transcriptional response to distal injury compared with AMs from young mice. Many changes were found to involve glucocorticoid-regulated genes, and corticosteroid treatment of primary AMs ex vivo revealed diminished transcriptional responses in cells from aged animals. These results demonstrate that there is a complex age-dependent AM phenotype associated with dysregulated stress hormone signaling that may interfere with AM responses to physiologic stressors and could contribute to AM dysfunction and the decline of pulmonary immunity during healthy aging.
肺泡巨噬细胞（AMs）是下呼吸道的组织驻留细胞，它们具有许多对于肺部健康和抵御病原体至关重要的稳态功能。然而，对于在健康衰老过程中塑造 AM 的因素知之甚少。在这些研究中，我们试图描述 AM 表型、功能以及对生理应激（即远端损伤）的反应随年龄的变化。年龄与 AM 表面受体和基因表达的广泛变化相关，反映了独特的替代性激活表型。与年轻对照相比，老年小鼠的 AM 还表现出细胞衰老的标志物，以及与生长和细胞周期途径相关的基因下调。此外，与年轻小鼠的 AM 相比，老年小鼠的 AM 对远端损伤的转录反应受到阻碍。许多变化被发现涉及糖皮质激素调节基因，并且体外原代 AM 的皮质类固醇处理显示出来自老年动物的转录反应减弱。这些结果表明，存在与应激激素信号转导失调相关的复杂的年龄依赖性 AM 表型，这可能会干扰 AM 对生理应激的反应，并可能导致 AM 功能障碍和肺部免疫在健康衰老过程中的下降。
