Microglia and Monocytes/Macrophages Polarization Reveal Novel Therapeutic Mechanism against Stroke

Masato Kanazawa, Itaru Ninomiya, Masahiro Hatakeyama, Tetsuya Takahashi, Takayoshi Shimohata, Masato Kanazawa, Itaru Ninomiya, Masahiro Hatakeyama, Tetsuya Takahashi, Takayoshi Shimohata

Abstract

Stroke is a leading cause of morbidity and mortality worldwide, and consists of two types, ischemic and hemorrhagic. Currently, there is no effective treatment to increase the survival rate or improve the quality of life after ischemic and hemorrhagic stroke in the subacute to chronic phases. Therefore, it is necessary to establish therapeutic strategies to facilitate functional recovery in patients with stroke during both phases. Cell-based therapies, using microglia and monocytes/macrophages preconditioned by optimal stimuli and/or any therapies targeting these cells, might be an ideal therapeutic strategy for managing stroke. Microglia and monocytes/macrophages polarize to the classic pro-inflammatory type (M1-like) or alternative protective type (M2-like) by optimal condition. Cell-based therapies using M2-like microglia and monocytes/macrophages might be protective therapeutic strategies against stroke for three reasons. First, M2-like microglia and monocytes/monocytes secrete protective remodeling factors, thus prompting neuronal network recovery via tissue (including neuronal) and vascular remodeling. Second, these cells could migrate to the injured hemisphere through the blood-brain barrier or choroid-plexus. Third, these cells could mitigate the extent of inflammation-induced injuries by suitable timing of therapeutic intervention. Although future translational studies are required, M2-like microglia and monocytes/macrophages therapies are attractive for managing stroke based on their protective functions.

Keywords: M2-like; macrophage; microglia; monocyte; pleiotropic effects; polarization; protective; stroke.

Conflict of interest statement

Takayoshi Shimohata is an academic adviser of the ShimoJani LLC biotech company. The other authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Scheme of M1-like or M2-like polarization. The M1-like responses as shown by the upregulation of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS). The M2-like responses as shown by the upregulation of markers such as arginase-1, chitinase-like protein 3 (also known as Ym1), cluster of differentiation (CD)206, CD163 and cytokines, IL-4, IL-10, transforming growth factor (TGF)-β, and growth factors. (a) Microglia and monocytes/macrophages polarize the M1-like state (classic, pro-inflammatory) following stroke, trauma, stimulation of lipopolysaccharide (LPS), interferon (IFN)-γ, TNF-α, or damage-associated molecular pattern (DAMP) through Toll-like receptor 4 (TLR4). The M1-like microglia and monocytes/macrophages would exacerbate inflammation and tissue damage. (b) Microglia and monocytes/macrophages polarize M2-like state (alternative, anti-inflammatory, protective) by protective cytokines and appropriate stimuli such as mild ischemia and drugs. Activation of triggering receptors expressed on myeloid cells 2 (TREM2) stimulates the phagocytic activity. Cell debris (dead cells) also stimulate microglia to polarize into the M2-like state. The M2-like microglia and monocytes/macrophages would suppress inflammation and prompt phagocytosis and tissue recovery. Abbreviations: BDNF, brain-derived neurotrophic factor; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor.
Figure 2
Figure 2
Dynamic polarized changes of microglia and monocytes/macrophages after stroke. (a) Temporal polarization changing by microglia and monocytes/macrophages after ischemic stroke by cell markers. The M1-like response exhibits an increasing trend in the first 14 days. The M2-like response exhibits a transient increasing trend in the first 1 to 2 days. Subsequently, the M2-like response exhibits a decreasing trend. However, it is unknown whether the M2-like response exhibits an increasing trend over the first 14 days. The balance of evidence supports an M2 to M1-like phenotype switch in the first 2 to 3 days. (b) Temporal polarization changing by microglia and monocytes/macrophages after hemorrhagic stroke. The M1-like response occurs as early as 6 h after hemorrhage, while the M2-like response starts to increase on day 1 after hemorrhage. Although a mixed M1- and M2-like microglial phenotype is evident during days 1 to 3, the balance of evidence supports an M1 to M2 phenotype switch in the first 7 days. The levels of most pro-inflammatory cytokines return to baseline on day 14. Abbreviations: mΦ, macrophage.
Figure 3
Figure 3
Illustration of the therapeutic effects of M2-like microglia and monocytes/macrophages. Abbreviations: BBB, blood-brain barrier.

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