Microglial Cells Contribute to Endogenous Brain Defenses after Acute Neonatal Focal Stroke

Abstract

Macrophages are viewed as amplifiers of ischemic brain injury, but the origin of injury-producing macrophages is poorly defined. The role of resident brain macrophages—microglial cells—in stroke remains controversial. To determine if microglial cells exert injurious effects after neonatal focal stroke, we selectively depleted these cells with intracerebral injection of liposome-encapsulated clodronate before transient middle cerebral artery occlusion in postnatal day seven rats. Phagocytosis of apoptotic neurons by activated microglia was poor in animals with unmanipulated microglia, and depletion of these cells did not increase the number of apoptotic neurons. Lack of microglia increased the brain levels of several cytokines and chemokines already elevated by ischemia–reperfusion, and also increased the severity and volume of injury, suggesting that microglial cells contribute to endogenous protection during the subacute injury phase. Then, to determine if accumulation of reactive oxygen species in microglia adversely affects phagocytosis of dying neurons and contributes to injury, we delivered reduced glutathione (GSH) into microglia, again using liposomes. Remarkably, pharmacologically increased intracellular GSH concentrations in microglia induced superoxide accumulation in lipid rafts in these cells, further increased the brain levels of macrophage chemoattractants, and exacerbated injury. Taken together, these data show that microglia are part of the endogenous defense mechanisms and that, while antioxidants can protect the injured neonatal brain, high levels of reducing equivalents in activated microglia, GSH, trigger superoxide production, favor the reorganization of lipids, amplify local inflammation and exacerbate injury.

Microglia/Macrophage Polarization Dynamics in White Matter after Traumatic Brain Injury

“…36 Among the potential factors that might have prevented their use in inflammatory conditions is that broad suppression of microglia/ macrophages may deprive the brain of their normal phagocytic roles and cause the buildup of cellular debris. This notion is supported by observations that selective depletion of proliferative microglia exacerbate brain injuries 24,37 and, conversely, that injections of exogenous microglia into the brain ameliorate CNS injuries. 38,39 Many authors have concluded that acute inflammation serves several protective functions, 16 whereas chronic inflammation exacerbates injury.…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…The depletion and replenishment of microglia were respectively augmented and reduced by N-methyl-D-aspartate-or oxygen glucose deprivation-induced neuronal cell death [61,62]. Faustino et al [63] also reported that microglia depletion enhances inflammation and injury in acute neonatal focal stroke. Selective ablation of proliferating microglia after focal ischemia in a transgenic mouse also demonstrated exacerbation of stroke injury with an altered inflammatory response [64].…”

Microglia activation in the extremely preterm human brain

“…Even though a recent study indicated that microglia exert a protective effect (13), most data suggest that they are injurious. It was proposed that the normal developmental increase in resident microglia renders the human neonatal periventricular white matter (PVWM) more susceptible to injury (6,8,14,15).…”