Objective Community-acquired pneumonia (CAP) is a leading cause of hospitalisation in older adults and is associated with a high likelihood of adverse outcomes. Given the ageing population and lack of therapeutic advances in CAP, new strategies to manage the burden of this disease are needed. Neutrophil dysfunction has been widely demonstrated in CAP and is associated with poor outcomes. We hypothesised that impaired glycolytic metabolism was driving neutrophil dysfunction in older adults with CAP. Methods To investigate the mechanism underlying neutrophil dysfunction in CAP, we recruited older adults with CAP and sepsis, age-matched controls and healthy young adults to assess neutrophil function and glycolytic metabolism in peripheral blood neutrophils. Results We demonstrate that neutrophils from older donors with CAP display a broad range of functional defects, including inaccurate migration to interleukin 8, impaired respiratory burst in response to phorbol 12-myristate 13-acetate and increased spontaneous degranulation compared with age-matched controls. Glycolysis (assessed by extracellular flux and RNA-sequencing) was not significantly altered between age-matched groups; however, basal rates of neutrophil glycolysis were significantly higher in patients with CAP and older adult controls compared with healthy young adults, and stimulated glycolysis was significantly higher in young adults compared with older adults with and without CAP. Conclusions Our findings suggest that neutrophil dysfunction in older adults with CAP may be implicated in poor outcomes, irrespective of glycolytic metabolism. Data are available in a public, open access repository. Data are available upon reasonable request. RNA sequencing data generated by this study were deposited into the Gene Expression Omnibus database under accession number GSE261559. Data are freely available. Other data are available upon reasonable request.

中文翻译：

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患有社区获得性肺炎和脓毒症的住院老年人中性粒细胞功能失调，但糖酵解正常


目的 社区获得性肺炎 （CAP） 是老年人住院的主要原因，与不良结局的可能性很高相关。鉴于人口老龄化和 CAP 治疗进展的缺乏，需要新的策略来管理这种疾病的负担。中性粒细胞功能障碍已在 CAP 中得到广泛证实，并且与不良结局相关。我们假设糖酵解代谢受损是导致 CAP 老年人中性粒细胞功能障碍的原因。方法 为了探讨 CAP 中性粒细胞功能障碍的机制，我们招募了患有 CAP 和脓毒症的老年人、年龄匹配的对照和健康的年轻人，以评估外周血中性粒细胞的中性粒细胞功能和糖酵解代谢。结果我们证明，来自患有 CAP 的老年供体的中性粒细胞表现出广泛的功能缺陷，包括向白细胞介素 8 的迁移不准确、对佛波醇 12-肉豆蔻酸酯 13-乙酸酯的反应呼吸爆发受损以及与年龄匹配的对照相比增加自发脱颗粒。年龄匹配的组之间的糖酵解（通过细胞外通量和 RNA 测序评估）没有显着改变;然而，与健康的年轻人相比，CAP 患者和老年人对照者的中性粒细胞糖酵解基础率显著更高，与有和没有 CAP 的老年人相比，年轻人的刺激糖酵解水平显著更高。结论 我们的研究结果表明，无论糖酵解代谢如何，CAP 老年人的中性粒细胞功能障碍可能与不良结局有关。数据在公共、开放访问存储库中可用。数据可根据合理要求提供。 本研究生成的 RNA 测序数据以 GSE261559 号存入 Gene Expression Omnibus 数据库。数据是免费提供的。其他数据可根据合理要求提供。