In the nervous system, glial cells, leaving only a 20-nm wide extracellular space filled with interstitial fluid, closely surround neurons. Ions transmitters, hormones, nutrients, and waste products all share this narrow diffusion pathway. Because the interstitial space occupies only a small volume, neuronal activity can lead to appreciable changes in the extracellular concentration of ions, protons, and neurotransmitters. These changes can affect neuronal activity and are believed to be influenced by glial cells. Despite advances in our comprehension of the molecular and functional repertories of microglia, important unanswered questions still remain. How do diverse and multiple receptors interact to determine the phenotypes and functions of reactive microglia? Could activation of microglia initiate the cascade of inflammatory events leading to recruitment of blood immune cells and stimulation of adaptive immune responses? Does the central nervous system (CNS) benefit from microglia activation? Is inappropriate or protracted activation of microglia proinflammatory and cytotoxic functions responsible for neuronal or myelin damage? Can microglia be activated to adopt an anti-inflammatory phenotype, and how? This review will highlight recent developments in our understanding of the molecular mechanisms of microglia function and new insights into the role played by microglia dysfunction in disease processes.
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