Abstract
Ischemic stroke is major cause of disability and mortality worldwide, and aging is strong risk factor for poor post-stroke outcome. Neutrophils traffic rapidly to the brain following ischemic stroke, and recent evidence has suggested that aging may alter neutrophil function after tissue injury. In this study, we hypothesize that aging enhances the pro-inflammatory function of neutrophils, directly contributing to the poorer outcomes seen in aging patients. We utilized demographic data and biological specimens from ischemic stroke patients and an experimental mouse model to determine the correlation between age, neutrophil function and stroke outcomes. In ischemic stroke patients, age was associated with increased mortality and morbidity and higher levels of neutrophil-activating cytokines. In mice, aged animals had higher stroke mortality and morbidity, higher levels of neutrophil-activating cytokines and enhanced generation of neutrophil reactive oxygen species compared to young mice. Finally, depletion of neutrophils via a specific monoclonal antibody after ischemic stroke led to long-term benefits in functional outcome in aged male and female animals, with no benefit observed in young. These results demonstrate that aging is associated with augmented neutrophil pathogenicity in ischemic stroke, and that neutrophil-targeted therapies may confer greater benefit in aged subjects.
Highlights
Stroke incidence increases dramatically with age, with the majority of strokes occurring in patients older than 65 years of age.[2]
We presented several mechanisms of neutrophil-induced tissue damage that may be critical to stroke, including their ability produce high levels of reactive species (ROS and reactive nitrogen species (RNS))
These results indicated that middle cerebral artery occlusion (MCAO) in aged mice is a good candidate model for the study of age-related neutrophil pathogenicity in ischemic stroke
Summary
Stroke incidence increases dramatically with age, with the majority of strokes occurring in patients older than 65 years of age.[2]. Our previous work has shown that aging has a significant impact on stroke outcome in mouse models and human patients.[96] The impact of aging on brain physiology and injury is multifactorial, involving systemic changes throughout the body in addition to alterations in the central nervous system itself.[118] Inflammation has been increasingly recognized as a significant driver of agerelated tissue dysfunction, a phenomenon known as “Inflammaging.”[119] Inflammaging is characterized by a gradual increase in pro-inflammatory immune activation as an organism ages, which is believed to be largely driven by cells of the innate immune system.[121] Inflammation is typically caused by tissue injury or pathogenic infection, and usually resolves once the pro-inflammatory stimulus has been eliminated.[120] During conditions of long-term or excessive inflammatory response, this resolution can fail, leading to a consistent state of non-productive, non-resolving inflammation. Many strategies have been employed to interfere with neutrophil activation, adhesion and transmigration, with promising animal results, yet none of the therapies that made it to clinical trials have shown any positive effect on patient outcome.[84, 176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194]
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