Regulation of Macrophage Phenotypes during Neuroinflammation and Stroke

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Mineralocorticoids have an important function during normal physiology, but increased mineralocorticoid receptor (MR) activation can cause or exacerbate a variety of diseases. Stroke is a major cause of mortality, and MR activation has a detrimental effect during ischemic stroke. MR antagonists provide beneficial effects during models of ischemic stroke independent of their blood pressure-lowering effects. We have recently shown that myeloid cells are critical targets for MR antagonists during ischemic stroke. However, cell-type- specific contribution of different myeloid cells and the mechanism by which myeloid MR exacerbates stroke is still unknown. Our laboratory has demonstrated that MR activation enhances pro-inflammatory, classical macrophage activation, whereas MR antagonism results in anti-inflammatory, alternative macrophage activation. We hypothesize that changes in macrophage activation are important in controlling the inflammatory component of stroke. The proposed studies will identify the cell-type-specific contributions and seek to identif the mechanisms by which myeloid MR activation exacerbates ischemic stroke. Furthermore, we will test whether we can enhance alternative macrophage activation with pharmacological synergy to provide additional neuroprotection during stroke.