Abstract
The concept of multiple macrophage activation states is not new. However, extending this idea to resident tissue macrophages, like microglia, has gained increased interest in recent years. Unfortunately, the research on peripheral macrophage polarization does not necessarily translate accurately to their central nervous system (CNS) counterparts. Even though pro- and anti-inflammatory cytokines can polarize microglia to distinct activation states, the specific functions of these states is still an area of intense debate. This review examines the multiple possible activation states microglia can be polarized to. This is followed by a detailed description of microglial polarization and the functional relevance of this process in both acute and chronic CNS disease models described in the literature. Particular attention is given to utilizing M2 microglial polarization as a potential therapeutic option in treating diseases.
Highlights
For the better part of a century, the function of microglia in the central nervous system (CNS) was a topic wrapped in controversy
Jimenez et al [132] observed at 6 months, when amyloid β (Aβ) begins to accumulate in the amyloid precursor protein (APP)/ PS1 Alzheimer’s disease mouse model, that there were YM1+ cells present in the CNS; by 18 months YM1 mRNA levels decreased and there was a massive upregulation in inflammatory factors, suggesting a switch from M2 to M1 as pathology worsened [132]
This is consistent with the idea that microglia become less responsive to M2 induction signals as they age, perhaps owing to an age-associated decrease in IL-4Rα levels [133]
Summary
For the better part of a century, the function of microglia in the central nervous system (CNS) was a topic wrapped in controversy. Jimenez et al [132] observed at 6 months, when Aβ begins to accumulate in the APP/ PS1 Alzheimer’s disease mouse model, that there were YM1+ cells present in the CNS; by 18 months YM1 mRNA levels decreased and there was a massive upregulation in inflammatory factors, suggesting a switch from M2 to M1 as pathology worsened [132] This is consistent with the idea that microglia become less responsive to M2 induction signals as they age, perhaps owing to an age-associated decrease in IL-4Rα levels [133]. In older, non-diseased mice there is downregulation of receptors associated with Aβ engulfment, such as scavenger receptor A and the Aβ degradation enzymes Nep, IDE, and MMP-9 [134] These observations suggest that the Aβ induced inflammatory environment, combined with age-associated effects on microglia, lead to a situation where M1 cells predominate and microglia lose the ability to switch phenotypes and mitigate damage. More work is needed to determine just what these populations represent
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