Abstract
Here we used mouse models of heart and brain ischemia to compare the inflammatory response to ischemia in the heart, a protein rich organ, to the inflammatory response to ischemia in the brain, a lipid rich organ. We report that ischemia-induced inflammation resolves between one and four weeks in the heart compared to between eight and 24 weeks in the brain. Importantly, we discovered that a second burst of inflammation occurs in the brain between four and eight weeks following ischemia, which coincided with the appearance of cholesterol crystals within the infarct. This second wave shares a similar cellular and molecular profile with atherosclerosis and is characterized by high levels of osteopontin (OPN) and matrix metalloproteinases (MMPs). In order to test the role of OPN in areas of liquefactive necrosis, OPN-/- mice were subjected to brain ischemia. We found that at seven weeks following stroke, the expression of pro-inflammatory proteins and MMPs was profoundly reduced in the infarct of the OPN-/- mice, although the number of cholesterol crystals was increased. OPN-/- mice exhibited faster recovery of motor function and a higher number of neuronal nuclei (NeuN) positive cells in the peri-infarct area at seven weeks following stroke. Based on these findings we propose that the brain liquefies after stroke because phagocytic cells in the infarct are unable to efficiently clear cholesterol rich myelin debris, and that this leads to the perpetuation of an OPN-dependent inflammatory response characterized by high levels of degradative enzymes.
Highlights
In response to ischemia, the brain degenerates by the process of liquefactive necrosis while the heart degenerates by coagulative necrosis (Robbins et al, 2010)
We have previously demonstrated that liquefactive necrosis is imperfectly segregated from uninfarcted brain tissue by glial scars and have provided evidence that it intensifies post-stroke injury in the weeks after stroke (Zbesko et al, 2018)
The reason why the brain undergoes liquefactive necrosis in response to ischemia, and why the infarct remains in a liquefactive state for weeks following stroke is unknown
Summary
The brain degenerates by the process of liquefactive necrosis while the heart degenerates by coagulative necrosis (Robbins et al, 2010). The goal of this research was to understand if the brain undergoes liquefactive necrosis in response to stroke due to the high cholesterol content of the brain The rationale for this is that in cardiovascular disease, atherosclerotic plaques develop within arteries when macrophages ingest excessive cholesterol (Moore et al, 2013). Foam cell formation is dictated by the balance between extracellular lipid uptake and reverse lipid transport from the intracellular compartment to extracellular lipid acceptors, such as high-density lipoprotein (HDL). When this balance tilts toward excessive cholesterol, it leads to cell death and chronic inflammation through multiple mechanisms
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