Review
Selective modulation of microglia polarization to M2 phenotype for stroke treatment

https://doi.org/10.1016/j.intimp.2015.02.019Get rights and content

Highlights

  • Microglia play a dual role in ischemic stroke.

  • In ischemic stroke, microglia show transient neuroprotective M2 phenotype followed by a shift to destructive M1 phenotype.

  • Multi-signal pathways regulating the alternation of microglial phenotype are reviewed.

  • Selective modulation of microglia polarization to M2 phenotype may be a possible therapeutic target for ischemic stroke.

Abstract

Resident microglia are the major immune cells in the brain, acting as the first defense of the central nervous system. Following cerebral ischemia, microglia respond to this injury at first and transform from surveying microglia to active state. The activated microglia play a dual role in the ischemic injury, due to distinct microglia phenotypes, including deleterious M1 and neuroprotective M2. However, microglia show transient M2 phenotype followed by a shift to M1. The high ratio of M1 to M2 is significantly related to ischemic injury. Many signal pathways participate in the alternation of microglial phenotype, presenting potential therapeutic targets for selectively modulating M2 polarization of microglia. In this review, we discuss how the M2 phenotype mediates neuroprotective effects and summarize the alternation of signaling cascades that control microglial phenotype after ischemic stroke.

Introduction

Ischemic stroke is the third leading cause of death and disability worldwide. The only effective treatment for ischemic stroke is the intravenous administration of tissue plasminogen activator (tPA), which benefits only patients who accept the treatment within a narrow time window after the stroke. There is no safe and effective therapy for patients who have missed the acute phase of the stroke, resulting in functional disability in surviving patients [1], [2]. Recent studies indicate that motor neuron death and suppression of hippocampal neurogenesis induced by activated microglia contribute to motor and cognitive dysfunction in amyotrophic lateral sclerosis (ALS), aging, and dementia [3], [4]. However, administration of exogenous microglia after ischemia improves ischemia-induced learning impairment [5]. Additionally, microglia have been proved to participate in neurogenesis after a stroke [6]. Thus, modulation of endogenous microglia may be beneficial for functional recovery, presenting a target for cerebral ischemia therapy.

Microglia, the brain-resident macrophages, are the major immune cells in ischemic injury [7], [8]. Under physiological conditions, microglia are characterized by ramified morphology and high motility, which make it convenient to monitor the microenvironment, prune synapse and timely clear apoptotic neurons to maintain the homeostasis of the central nervous system (CNS) [9], [10], [11]. Neuron injury induced by cerebral ischemia contributes to microglial activation by increasing the levels of ATP, heat shock proteins 60 (HSP60) and glutamate [12]. Microglia are de-ramified after activation and rapidly change their phenotype, mediating neuroprotective or inevitable detrimental effects. As shown in Table 1, two phenotypes have been used to identify activated microglia. M1 represents a detrimental state of microglia, characterized by high expression of pro-inflammatory mediators including interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), propelling the pathological process of cerebral ischemia. Conversely, the M2 phenotype prolongs neuron survival and restricts brain damage after ischemic injury associated with high levels of arginase-1 (Arg-1), interleukin-10 (IL-10), transforming growth factor beta (TGF-β) and insulin-like growth factor-1 (IGF-1) (Table 1) [13], [14]. However, activated microglia show the transient M2 phenotype followed by a shift to the detrimental M1 phenotype after cerebral ischemia [15]. A selective inhibition of M1 microglia by minocycline can obviously ameliorate ischemic damage by decreasing inflammatory response [16], [17]. Therefore, selectively increasing M2 polarization of microglial cells may be a potential strategy of stroke treatment. Thus, we make a review about the neuroprotective effects of the M2 phenotype, the process and the possible mechanisms of microglial polarization after cerebral ischemia.

Section snippets

M2 phenotype facilitates phagocytosis of debris induced by cerebral ischemia

Clearance of apoptotic and necrotic cells by microglia is particularly important to maintain homeostasis of CNS under pathological conditions. Removal of damaged neurons can not only prevent secondary inflammatory reaction, but also make space for newborn neurons and reconstruct homeostasis benefiting the survival of newborn neurons. The best “eat-me” signal from neurons is phosphatidylserine (PS) exteriorization. Recognition of PS is equipped with an array of receptors, as shown in Table 2 [18]

Response of microglia after cerebral ischemia

After cerebral ischemia, microglia display various changes over time, including morphology, phenotype and productions. Ischemia-induced dying neurons release ATP, activating microglia through P2 receptors. Correspondingly, the expression of P2X4 and P2X7 receptors on microglia are increased significantly after ischemia [49], [50]. Activated microglia are accumulated in the injury region. Many factors participate in the migration of microglia towards the injury site and ATP is one of the

Mechanism of microglial phenotype transition

Ischemia changes the microenvironment of microglia and activate microglia. Current studies emphasize that crosstalk of intracellular signal regulations determine the state of microglia [12], [60], [61]. In the following sections, we discuss the networks and alternation of transcription factors associated with ischemia-induced polarization of microglia, as shown in Table 3.

Conclusion

Microglia act as the first line of defense in the brain, play an irreplaceable role in maintaining brain homeostasis. In response to micro-environmental changes, microglia show dynamic phenotypes, shifting from M2 phenotype to M1 phenotype after cerebral ischemia, which may contribute to the pathology process of ischemic stroke. Compared with the M1 phenotype, the M2 phenotype has a stronger capacity to elicit phagocytosis of dead neurons to avoid prevent secondary inflammatory response and

Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 81274122, No. 81173578, No. 81102831, No. 81373997), National Key Sci-Tech Major Special Item (No. 2012ZX09301002-004, No. 2012ZX09103101-006), National 863 Program of China (No. 2012AA020303), Beijing Natural Science Foundation (No. 7131013), and Research Fund for the Doctoral Program of Higher Education of China (No. 20121106130001).

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