Role of zinc in microglial phenotypes

Abstract

Microglia are resident immune cells of the central nervous system (CNS) that continuously survey the local microenvironment by extending and withdrawing their cellular processes in the resting state. When activated by tissue injury or other signals, microglia retract their processes and transform into an activated amoeboid morphology. These activated cells are known to polarize into M1 pro-inflammatory or M2 anti-inflammatory phenotypes during neuropathological conditions, including stroke, which suggests that this polarization might play a role in the development and progression of brain disorders. Furthermore, zinc homeostasis in the CNS is integral to normal CNS function, such as learning and memory. Although the effects of zinc on microglial activation are not well known, recent studies have demonstrated that zinc affects microglial activation as well as neuronal function. In this review, we discuss in detail the effects of extracellular and intracellular zinc levels on microglial activation and the M1 and M2 microglial phenotypes. Extracellular zinc might act as a novel trigger for the microglial morphological changes via a zinc-induced microglial activation signaling pathway, where intracellular zinc accumulation via Zrt-Irt-like protein 1 is the initial step. Additionally, extracellular zinc might promote the inflammatory M1 phenotype, while increased intracellular free zinc levels in interleukin-4-induced M2a microglia might negatively regulate arginase-1 expression. The zinc-promoted M1 phenotype is involved in post-ischemic cognitive decline and suppression of astrocytic engulfing activity, whereas zinc-modulated arginase-1 expression might regulate the phagocytic activity of M2a microglia.

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