Although microglia have long been considered as brain resident immune cells, increasing evidence suggests that they also have physiological roles in the development of the normal CNS. In this study, we found large numbers of activated microglia in the forebrain subventricular zone (SVZ) of the rat from P1 to P10. Pharmacological suppression of the activation, which produces a decrease in levels of a number of proinflammatory cytokines (i.e., IL-1, IL-6, TNF-␣, and IFN-␥) significantly inhibited neurogenesis and oligodendrogenesis in the SVZ. In vitro neurosphere assays reproduced the enhancement of neurogenesis and oligodendrogenesis by activated microglia and showed that the cytokines revealed the effects complementarily. These results suggest that activated microglia accumulate in the early postnatal SVZ and that they enhance neurogenesis and oligodendrogenesis via released cytokines.
Severe neuroinflammation is associated with blood brain barrier (BBB) disruption in CNS diseases. Although microglial activation and the subsequent changes in cytokine/chemokine (C/C) concentrations are thought to be key steps in the development of neuroinflammation, little data are available concerning the interaction of microglia with BBB cells. In this study, we investigated this interaction by adding LPS-activated microglia (LPS-MG) to the abluminal side of a BBB model composed of endothelial cells (EC), pericytes (Peri) and astrocytes (Ast). We then examined the abluminal concentrations of 27 C/Cs and the interactions between the LPS-MG and BBB cells. LPS-MG caused collapse of the BBB, revealed by decreases in the trans-endothelial electrical resistance (TEER) and by changes in the expression levels of tight junction (TJ) proteins. Under these conditions, 19 C/Cs were markedly increased on the abluminal side. Unexpectedly, although LPS-MG alone released 10 of the 19 C/Cs, their concentrations were much lower than those detected on the abluminal side of the BBB model supplemented with LPS-MG. Co-culture of LPS-MG with Ast caused marked increases in 12 of the 19 C/Cs, while co-culture of LPS-MG with EC and Peri resulted in a significant increase in only 1 of the 19 C/Cs (fractalkine). These results suggest that C/C dynamics in this system are not only caused by activated microglia but also are due to the interaction between activated microglia and astrocytes.
-Although carbon nanotubes (CNTs) are used in many fields, including energy, healthcare, environmental technology, materials, and electronics, the adverse effects of CNTs in the brain are poorly understood. In this study, we investigated the effects of CNTs on cultured microglia, as microglia are the first responders to foreign materials. We compared the effects of sonicated suspensions of 5 kinds of CNTs and their flow-through filtered with a 0.22 μm membrane filter on microglial viability. We found that sonicated suspensions caused microglial cell damage, but their flow-through did not. The number of microglial aggregates was well correlated with the extent of the damage. We also determined that the CNT agglomerates consisted of two groups: one was phagocytosed by microglia and caused microglial cell damage, and the other caused cell damage without phagocytosis. These results suggest that phagocytosis-dependent and independent mechanisms underlie the microglial cell damage caused by CNT agglomerates and it is important to conduct studies about the relationships between physical properties of nanomaterial-agglomerates and cell damage.
The blood-brain barrier (BBB) restricts the transport of substances between vasculature and brain. Recent studies have clarified that various kinds of cells in neurovascular unit are related to the BBB functions. In this study, we investigated the roles of microglia in BBB functional maturation using in vitro BBB model comprised of endotherial cells, pericytes, and astrocytes (Ⓒpharmacocell). When we added primary microglia to the brain side of the model during the maturation period, trans-endothelial electrical resistance (TEER) and the expression level of claudin-5, were significantly increased. On the other hand, when we added LPS-activated microglia, the TEER and the expression levels of tight junction proteins (TJs) were significantly decreased. We next investigated involvement of cytokines/chemokines in the effects of microglia. We clarified that microglia-induced increase in TEER was mediated by VEGF, while the increases in TJs were mediated by the inhibition of fractalkine signaling. In the developing brain, a lot of microglia surroud the capillaries. Our data suggest that microglia contribute to the developmental maturation of the BBB. We are currently investigating the accurate time course of BBB maturation and the roles of microglia in the BBB maturation at the developmental stage by in vivo experiments.
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