Abstract
Ischemic stroke (caused by thrombosis, embolism or vasoconstriction) lead to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral macrophages, which contribute to an inflammatory response involved in regulation of the neuronal damage. We showed earlier that upon pro-inflammatory stimuli, the orderly activation of caspase-8 and caspase-3/7 regulates microglia activation through a protein kinase C-δ dependent pathway. Here, we present in vivo evidence for the activation of caspase-8 and caspase-3 in microglia/macrophages in post-mortem tissue from human ischemic stroke subjects. Indeed, CD68-positive microglia/macrophages in the ischemic peri-infarct area exhibited significant expression of the cleaved and active form of caspase-8 and caspase-3. The temporal and spatial activation of caspase-8 was further investigated in a permanent middle cerebral artery occlusion mouse model of ischemic stroke. Increasing levels of active caspase-8 was found in Iba1-positive cells over time in the peri-infarct area, at 6, 24 and 48 h after artery occlusion. Analysis of post-mortem brain tissue from human subject who suffered two stroke events, referred as recent and old stroke, revealed that expression of cleaved caspase-8 and -3 in CD68-positive cells could only be found in the recent stroke area. Analysis of cleaved caspase-8 and -3 expressions in a panel of human stroke cases arranged upon days-after stroke and age-matched controls suggested that the expression of these caspases correlated with the time of onset of stroke. Collectively, these data illustrate the temporal and spatial activation of caspase-8 and -3 in microglia/macrophages occurring upon ischemic stroke and suggest that the expression of these caspases could be used in neuropathological diagnostic work.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0365-9) contains supplementary material, which is available to authorized users.
Highlights
Every year, an estimate of 15 million people worldwide suffers a stroke
We investigated in vivo and in post-mortem tissue from ischemic stroke subjects whether caspase-8 and caspase-3 activation, key players of the caspase-dependent signaling pathways regulating microglia and macrophages (MMs) pro-inflammatory activation, exhibited spatiotemporal features upon ischemic stroke
The brain's inflammatory response post-ischemia is characterized by several stages, which is reflected in the recruitment and activation state of the involved immune cells
Summary
An estimate of 15 million people worldwide suffers a stroke. Nearly six million people die and an almost equal number of survivors are left with long-term disabilities [1, 2]. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic,. A decrease or reduction in blood flow results in hypoxia and glucose deprivation, which can lead to neuronal damage and cell death. The center of the ischemic area, the ischemic core, is most affected by the reduction in blood flow and suffers the more instant and severe damage of the tissue. The area surrounding the ischemic region, the penumbra, can receive low levels of blood flow from adjacent vascularized areas, resulting in slower
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