https://www.biorxiv.org/content/early/2018/02/16/264275
Abstract
The
response to ischemic injury in the brain is different to the response
to ischemic injury in other organs and tissues. Almost exclusive to the
brain, and for unknown reasons, dead tissue liquefies in response to
ischemia by the process of liquefactive necrosis. However, the data we
present here indicate that at the macroscopic, microscopic, and
molecular level, liquefactive necrosis strongly resembles
atherosclerosis. We show that chronic stroke infarcts contain foamy
macrophages, cholesterol crystals, high levels of osteopontin and matrix
metalloproteinases, and a similar cytokine profile to atherosclerosis.
Excessive cholesterol loading of macrophages is a principal driver of
atherosclerosis. Therefore, because cholesterol is an important
structural component of myelin, liquefactive necrosis in response to
stroke may be caused by an inflammatory response to myelin debris that
is prolonged by the formation of cholesterol crystals within
macrophages. We propose that this results in the chronic production of
high levels of proteases, which in a partially osteopontin dependent
mechanism, causes secondary neurodegeneration and encephalomalacia of
the surrounding tissue. In support of this, we show that genetically
ablating osteopontin substantially reduces the production of degradative
enzymes following stroke, reduces secondary neurodegeneration, and
improves recovery. These findings suggest that treatments that prevent
atherosclerosis or target the regression of atherosclerosis may also be
useful for mitigating the harmful effects of liquefactive necrosis
following stroke.
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