Perivascular microglia promote blood vessel disintegration in the ischemic penumbra

Abstract

The contribution of microglia to ischemic cortical stroke is of particular therapeutic interest because of the impact on the survival of brain tissue in the ischemic penumbra, a region that is potentially salvable upon a brain infarct. Whether or not tissue in the penumbra survives critically depends on blood flow and vessel perfusion. To study the role of microglia in cortical stroke and blood vessel stability, CX3CR1(+/GFP) mice were subjected to transient middle cerebral artery occlusion and then microglia were investigated using time-lapse two-photon microscopy in vivo. Soon after reperfusion, microglia became activated in the stroke penumbra and started to expand cellular protrusions towards adjacent blood vessels. All microglia in the penumbra were found associated with blood vessels within 24 h post reperfusion and partially fully engulfed them. In the same time frame blood vessels became permissive for blood serum components. Migration assays in vitro showed that blood serum proteins leaking into the tissue provided molecular cues leading to the recruitment of microglia to blood vessels and to their activation. Subsequently, these perivascular microglia started to eat up endothelial cells by phagocytosis, which caused an activation of the local endothelium and contributed to the disintegration of blood vessels with an eventual break down of the blood brain barrier. Loss-of-microglia-function studies using CX3CR1(GFP/GFP) mice displayed a decrease in stroke size and a reduction in the extravasation of contrast agent into the brain penumbra as measured by MRI. Potentially, medication directed at inhibiting microglia activation within the first day after stroke could stabilize blood vessels in the penumbra, increase blood flow, and serve as a valuable treatment for patients suffering from ischemic stroke.

Role of Sortilin in Models of Autoimmune Neuroinflammation

“…Although there is certainly an inflammatory component in stroke, it is not as prevalent as in classical neuroinflammatory diseases, and the innate and adaptive immune systems play different roles at different time points following acute injury (20,26) than do those in classic neuroinflammation. In summary, we showed that sortilin is expressed in different immune cell populations, including DCs, where it is involved in Ag processing.…”

Role of neuroinflammation in ischemic stroke

“…[81] These activated microglia start to engulf endothelial cells via phagocytosis, which allows the entrance of blood serum components. [82] Active microglia phagocytoses foreign organisms as well as injured brain cells. [60,83] In ischemic stroke, activation of microglia is the early stages of the neuroinflammation process even within minutes.…”

MicroRNA-Let-7a regulates the function of microglia in inflammation

“…In response to any stimulus, microglia indicates a variety of responses that includes morphological alterations (Minten et al, 2012), migration to the site of injury (Jolivel et al, 2014;Yu et al, 2014), and increased expression of various factors such as cytokines (Kim et al, 2014;Skaper et al, 2014). Moreover, microglia transform into phagocytic cells; removing dead cells, protein aggregates, and viral pathogens (Hanisch and Kettenmann, 2007).…”