Aging aggravates ischemic stroke-induced brain damage in mice with chronic peripheral infection

Abstract

SummaryIschemic stroke is confounded by conditions such as atherosclerosis, diabetes, and infection, all of which alter peripheral inflammatory processes with concomitant impact on stroke outcome. The majority of the stroke patients are elderly, but the impact of interactions between aging and inflammation on stroke remains unknown. We thus investigated the influence of age on the outcome of stroke in animals predisposed to systemic chronic infection. Th1-polarized chronic systemic infection was induced in 18-22 month and 4-month-old C57BL/6j mice by administration of Trichuris muris (gut parasite). One month after infection, mice underwent permanent middle cerebral artery occlusion and infarct size, brain gliosis, and brain and plasma cytokine profiles were analyzed. Chronic infection increased the infarct size in aged but not in young mice at 24 h. Aged, ischemic mice showed altered plasma and brain cytokine responses, while the lesion size correlated with plasma prestroke levels of RANTES. Moreover, the old, infected mice exhibited significantly increased neutrophil recruitment and upregulation of both plasma interleukin-17a and tumor necrosis factor-a levels. Neither age nor infection status alone or in combination altered the ischemia-induced brain microgliosis. Our results show that chronic peripheral infection in aged animals renders the brain more vulnerable to ischemic insults, possibly by increasing the invasion of neutrophils and altering the inflammation status in the blood and brain. Understanding the interactions between age and infections is crucial for developing a better therapeutic regimen for ischemic stroke and when modeling it as a disease of the elderly.

Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice

“…This hypothesis is supported by studies reporting the effects of chronic peripheral infection and systemic inflammation induced by lipopolysaccharide (LPS) in the aged brain. Aged mice infected with a parasite Trichuris muris, which upregulates systemic proinflammatory cytokines, have an increase in infarct volumes with exaggerated infiltration of neutrophils in the ischemic brain compared with those of young mice (Dhungana et al, 2013). In LPS-treated aged mice, inflammatory responses in the brain are extensive, and sickness behavior is more prolonged compared with the young animals (Hart et al, 2012;Koenig et al, 2014).…”

Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation

“…Magnetic resonance imaging (MRI) was used to determine the infarct volume in vivo at 24 h or 72 h post ischemia using a vertical 9.4 T Oxford NMR 400 magnet (Oxford Instrument PLC, Abington, UK) as previously described (Dhungana et al, 2013a). In brief, the mice were anesthetized as above and multislice T2-weighted images (repetition time 3000 ms, echo time 40 ms, matrix size 128 Â 256, field of view 19.2 Â 19.2 mm 2 , slice thickness 0.8 mm and number of slices 12) were obtained.…”

Astrocytic response to cerebral ischemia is influenced by sex differences and impaired by aging

“…The accelerated development of degenerating neurons and apoptotic cells following ischemia in males may contribute to the poorer outcomes (Popa-Wagner et al, 2007). There is also evidence that chronic infection resulting in pre-existing inflammation, a condition known to influence stroke outcome, results in increased infarct size in aged male mice but not in young mice 24 h post stroke (Dhungana et al, 2013). Importantly, some studies have found opposite effects of aging or no effects of aging in male mice following ischemia.…”