Role of M2-type macrophage-specific modulation in a time-dependent manner against post-ischemic brain damage in rat

Abstract Background Cerebral ischemia triggers inflammatory changes, and early complications and unfavorable outcomes of endovascular thrombectomy for brain occlusion promote the recruitment of various cell types to the ischemic area. Although phenotype-specific monocytes/macrophages appear to play a role, the detailed effects remain unclear. To test our hypothesis that post-ischemic phase-dependent modulation of macrophages may represent a potential therapy against ischemic brain damage, we studied the significance of inducing anti-inflammatory M2-type, but not pro-inflammatory M1-type, macrophages after brain ischemia. Methods Seven-week-old male Wistar rats subjected to middle cerebral artery occlusion-reperfusion (MCAO-R) were treated for 7 days with an activator of M2-type macrophages, Gc-protein macrophage-activating factor (GcMAF), in the acute (day 0–6) or subacute (day 7–13) phase after ischemia induction and compared with vehicle-treated control rats. Results In MCAO-R rats, brain damage expansion elicited by increased mRNA levels of interleukin (IL)-6 and IL-1β abated on day 7. Acute-phase GcMAF treatment augmented anti-inflammatory CD163+ M2-type- and pro-inflammatory CD16+ M1-type macrophages, resulting in no beneficial effects. During days 7–14, GcMAF injection increased only CD163+ M2-type macrophages accompanied by elevated mRNA levels of arginase-1 and IL-4. M2-type macrophages co-localized with CD36+ phagocytic cells led to clearance of the infarct area which was abrogated by clodronate-liposomes. Finally, the expression of survival-related molecules on day 28 was augmented in the infarct border, suggesting that activation of M2-type macrophages in the subacute post-ischemia phase may play a therapeutic role. Conclusion Our findings require further studies to assess the time-dependent therapeutic significance of M2-type-macrophages against cerebral ischemia.