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Abstract T P70: Resolving the Relative Contribution of Resident Microglia versus Infiltrating Macrophages in the Ischemic Brain After Stroke


 Introduction:
 Early after stroke local inflammatory changes are primarily mediated by microglia, the resident macrophages of the brain. As injury evolves and the vascular integrity becomes compromised, there is a robust infiltration of peripheral myeloid cells into the ischemic area. Given the common lineage ancestry and morphological similarity between bone marrow-derived (BM) macrophages and resident microglia, the two cell types become nearly indistinguishable from each other using standard immunohistological methods. To date, the most sensitive means of discerning between microglia and BM macrophages relies on the relative level of CD45 expression. In this study, ex-vivo analyses were performed to distinguish CD45intCD11b+ microglia and CD45hiCD11b+Ly6C+ BM macrophages. Functional studies were also performed.
 
 
 Materials & Methods:
 Young male C57Bl/6 mice were subject to sham surgery or middle cerebral artery occlusion for 90min followed by 72hr or 7d of reperfusion. Ipsilateral hemispheres were harvested from PBS perfused mice and fixed for immunohistological preparation or processed by dissociation into single cell suspensions for use in functional flow cytometry assays.
 
 
 Results:
 Significant microglia cell death occurred by 72hr, and inversely correlated with BM macrophage infiltration. Surviving microglia showed a low rate of proliferation in response to ischemic stress compared to BM macrophages (1% vs. 7%; p<0.01). Peripheral macrophages were the primary source of TNF, while IL-1β was predominately expressed by microglia. Mitochondrial activity was significantly altered in microglia after stroke (p<0.05) and was accompanied by two-fold increases in ROS production. Finally, microglia displayed poor phagocytic potential after stroke compared to infiltrating macrophages (12% vs. 30%; p<0.01).
 
 
 Discussion:
 There is a complex, biphasic macrophage response to stroke injury. The post-acute phase is characterized by widespread microglia activation and dysregulation, whereas the subsequent resolution phase consists of debris clearance in the necrotic core by infiltrating macrophages.
