Spatial transcriptomic analysis reveals dysregulated pro-inflammatory signaling in the aged lung

Older individuals are more susceptible to viral and bacterial respiratory infections than younger people. While structural lung changes and a hyperinflammatory milieu have been proposed to contribute to worsened clinical outcomes, exact mechanisms remain elusive. Clinical specimens are challenging to obtain and although rodents are valuable models of human disease, their specific pathogen free status and inbred genetics limit translation of findings obtained from these models. We sought to address this question by analyzing the transcriptional landscape of lung tissue obtained from young and aged rhesus macaque using Visium spatial transcriptomics. Unlike rodents, captive rhesus macaques are genetically outbred and exposed to natural particulates and respiratory microbes that modulate their lung immunity. Analysis identified immune and structural cells clusters. Differential gene expression revealed a strong pro-inflammatory bias in aged animals while transcriptional signatures in young animals were consistent with a regulatory phenotype. Moreover, cellular signaling important for adhesion, tissue maintenance, and cell migration was significantly reduced in the aged compared to young lungs. These data indicate that aged lungs are skewed towards hyperinflammatory responses which are likely to result in higher immune mediated damage following challenge.

相较于年轻人，老年人更易受病毒与细菌性呼吸道感染的侵袭。尽管已有研究提出肺部结构改变与炎症反应过度的微环境可能是临床结局恶化的诱因，但具体致病机制仍不明晰。临床标本的获取颇具挑战；尽管啮齿类动物（rodents）是研究人类疾病的经典模型，但其无特定病原体（specific pathogen free, SPF）饲养背景与近交遗传特性，限制了该类模型所得研究结果的转化应用。本研究旨在通过采用Visium空间转录组学（Visium spatial transcriptomics）技术，分析青年与老年恒河猴（rhesus macaque）肺组织的转录组全景，以解答这一科学问题。与啮齿类动物不同，圈养恒河猴具有远交遗传背景，且会暴露于可调节肺部免疫功能的天然颗粒物与呼吸道微生物环境中。本次转录组分析成功鉴定出免疫细胞与肺结构细胞的细胞簇。差异基因表达分析结果显示，老年恒河猴肺部呈现显著的促炎偏向；而青年恒河猴的转录特征则与调节型表型相符。此外，相较于青年恒河猴肺组织，老年个体肺组织中参与细胞黏附、组织稳态维持与细胞迁移的关键细胞信号通路活性显著降低。上述研究结果表明，老年恒河猴的肺组织偏向于产生过度炎症反应，这可能使其在受到感染刺激后更容易出现免疫介导的组织损伤。