Ischemic stroke is a leading cause of morbidity and mortality in the world, and inflammation can have a significant impact on stroke severity.Sustained inflammation after stroke can have detrimental effects; however, certain inflammatory cell types and mediators can also produce beneficial effects.Mineralocorticoid Receptor (MR) antagonists are used clinically to treat heart failure and also have beneficial effects in preclinical models of stroke independent of blood pressure lowering.MR has been shown to regulate macrophage activation and polarization, and MR antagonists can induce an anti-inflammatory, alternative macrophage phenotype.In this dissertation, we show that genetic ablation of MR in myeloid cells is neuroprotective during ischemic stroke. We demonstrate that myeloid MR inactivation significantly reduces infarct volume and suppresses the pro-inflammatory response to stroke.This delineates a previously unknown mechanism of pharmacological control by MR antagonists during stroke.Neuroprotection by myeloid MR knockout occurs within two hours after reperfusion and was detected in a transient ischemia-reperfusion model, but not during permanent occlusion.In contrast to previously defined sexual dimorphic effects of MR antagonists during stroke, myeloid MR knockout ameliorates cerebral ischemia-reperfusion in both males and females.These data define a novel role for myeloid MR during stroke, and demonstrate the importance of MR-regulated myeloid cell phenotypes during the inflammatory response to stroke.
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Protection from Stroke through Immunomodulatory Mechanisms.
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