ba9db974-study
Lung imaging reveals stroke-induced impairment in pulmonary intravascular neutrophil function, a response exacerbated with aging
In stroke patients, infection is a significant contributor to morbidity and mortality. Moreover, older stroke patients show an increased risk of developing stroke-associated infection, although the mechanisms underlying this increased susceptibility to infection are unknown. Here, using an experimental mouse model of ischemic stroke, we showed that older (12-15 months) mice had elevated lung bacterial infection and inflammatory damage after stroke when compared to young (8-10 weeks) counterparts, despite undergoing the same degree of brain injury. Intravital microscopy of the lung microvasculature revealed that in younger mice, stroke promoted neutrophil arrest in pulmonary microvessels, but this response was not seen in older post-stroke mice. In addition, bacterial phagocytosis by neutrophils in the lung microvasculature was reduced by both aging and stroke, such that neutrophils in aged post-stroke mice showed the greatest impairment in this function. Analysis of neutrophil migration *in vitro* and in the cremaster muscle demonstrated that stroke alone did not negatively impact neutrophil migration, but that combination of increased age and stroke led to reduced effectiveness of neutrophil chemotaxis. Transcriptomic analysis of pulmonary neutrophils using RNA-seq identified 79 genes that were selectively altered in the context of combined aging and stroke, and they were associated with pathways that control neutrophil chemotaxis. Together, the findings of this study show that stroke in older animals results in worsening of neutrophil antibacterial responses and changes in neutrophil gene expression that have the potential to underpin elevated risk of stroke-associated infection in the context of increased age.
In stroke patients, infection is a significant contributor to morbidity and mortality. Moreover, older stroke patients show an increased risk of developing stroke-associated infection, although the mechanisms underlying this increased susceptibility to infection are unknown. Here, using an experimental mouse model of ischemic stroke, we showed that older (12-15 months) mice had elevated lung bacterial infection and inflammatory damage after stroke when compared to young (8-10 weeks) counterparts, despite undergoing the same degree of brain injury. Intravital microscopy of the lung microvasculature revealed that in younger mice, stroke promoted neutrophil arrest in pulmonary microvessels, but this response was not seen in older post-stroke mice. In addition, bacterial phagocytosis by neutrophils in the lung microvasculature was reduced by both aging and stroke, such that neutrophils in aged post-stroke mice showed the greatest impairment in this function. Analysis of neutrophil migration *in vitro* and in the cremaster muscle demonstrated that stroke alone did not negatively impact neutrophil migration, but that combination of increased age and stroke led to reduced effectiveness of neutrophil chemotaxis. Transcriptomic analysis of pulmonary neutrophils using RNA-seq identified 79 genes that were selectively altered in the context of combined aging and stroke, and they were associated with pathways that control neutrophil chemotaxis. Together, the findings of this study show that stroke in older animals results in worsening of neutrophil antibacterial responses and changes in neutrophil gene expression that have the potential to underpin elevated risk of stroke-associated infection in the context of increased age.