Neuroscience
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Microglial cells are now recognized as the "gate-keepers" of healthy brain microenvironment with their disrupted functions adversely affecting neurovascular integrity, neuronal homeostasis, and network connectivity. The perception that these cells are purely toxic under neurodegenerative conditions has been challenged by a continuously increasing understanding of their complexity, the existence of a broad array of microglial phenotypes, and their ability to rapidly change in a context-dependent manner to attenuate or exacerbate injuries of different nature. ⋯ We further discuss context-dependent microglial contribution to neonatal brain injuries associated with prenatal and postnatal infection and inflammation, in relation to neurodevelopmental disorders, as well as perinatal hypoxia-ischemia and arterial focal stroke. We also emphasize microglial phenotypic diversity, notably at the ultrastructural level, and their sex-dependent influence on the pathophysiology of neurodevelopmental disorders.
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Over the past few decades, microglial cells have been regarded as the main executor of inflammation after acute and chronic central nervous system (CNS) disorders, responding rapidly to exogenous stimuli during acute trauma or infections, or signals released by cells undergoing cell death during conditions such as stroke, Alzheimer's disease (AD) and Parkinson's disease (PD). Barriers of the nervous system, and in particular the blood-brain barrier (BBB), play a key role in the normal physiological and cognitive functions of the brain. ⋯ This involves a dynamic response mediated by all components of the neurovascular unit (NVU), and ongoing research suggests that BBB-microglia interaction is critical to dictate the microglial response to NVU injury. The present review aims to give an up-to-date account of the emerging critical role of BBB-microglia interactions during neuroinflammation, and how these could be targeted for the therapeutic treatment of major central inflammatory disease.
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Microglia are instrumental for recognition and elimination of amyloid β1-42 oligomers (AβOs), but the long-term consequences of AβO-induced inflammatory changes in the brain are unclear. Here, we explored microglial responses and transciptome-level inflammatory signatures in the rat hippocampus after chronic AβO challenge. Middle-aged Long Evans rats received intracerebroventricular infusion of AβO or vehicle for 4 weeks, followed by treatment with artificial CSF or MCC950 for the subsequent 4 weeks. ⋯ Furthermore, MCC950 abrogated AβO-invoked reduction of serum IL-10. These findings provide evidence that in response to AβO infusion microglia change their phenotype, but the resulting inflammatory changes are sustained for at least one month after the end of AβO challenge. Lasting NLRP3-driven inflammatory alterations and altered hippocampal gene expression contribute to spatial memory decline.
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Brain injury is associated with neuroinflammation, and microglia are key players in this process. Microglia can acquire pro-inflammatory or anti-inflammatory properties, but how this affects neural stem cells (NSCs) remains controversial. Here, NSCs were grown in conditioned media collected from either non-stimulated microglia, or microglia stimulated with pro- or anti-inflammatory agents. ⋯ We found that NSCs kept in conditioned medium from the anti-inflammatory microglial subtype had better survival, increased migration, and lower astrocytic differentiation compared to NSCs grown in conditioned medium collected from the pro-inflammatory subtype. Finally, we found that NSCs differentiated in microglial conditioned media generated cells expressing the pro-inflammatory chemokine CCL2, most pronounced when differentiated in medium from the pro-inflammatory microglia subtype. Our results show that microglial subtypes regulate NSCs differently and induce generation of cells with inflammatory properties.