Hospitalised older adults with community-acquired pneumonia and sepsis have dysregulated neutrophil function but preserved glycolysis

Abstract

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.