Microglia Polarization in Ischemic Stroke: Complex Mechanisms and Therapeutic Interventions
Stroke is the second leading cause of death globally and the third leading contributor to the loss of disability-adjusted life-years. The fatality rate of stroke patients ranges from 15% to 50% within one month to five years after the event. Ischemic stroke, which accounts for 87% of all stroke cases, is the most common type of stroke. Microglia, the resident tissue macrophages in the central nervous system (CNS), play a crucial role in the brain’s response to ischemic stroke. These cells act as sentinels, surveying the CNS every 2 to 3 hours. When an ischemic stroke occurs, microglia are rapidly recruited to the damaged sites, serving as the first line of defense in the CNS. The activation of microglia is influenced by various brain stimuli, leading to either tissue damage or repair. Microglia can acquire diverse phenotypes in response to different types of activation, exhibiting specific biomarkers and exerting distinct biological functions, including proinflammatory and anti-inflammatory activities. The phenotypic transition of microglia is common during the inflammatory response.
Microglial Polarization States
Microglia, similar to macrophages, can be activated under different circumstances and exhibit either proinflammatory or anti-inflammatory properties. Microglia can be polarized into a proinflammatory state (M1) by stimuli such as lipopolysaccharide (LPS) or interferon gamma (IFN-g), or into an anti-inflammatory state (M2) by interleukin 4 (IL-4), IL-10, or IL-13. M1 microglia release proinflammatory factors, while M2 microglia release anti-inflammatory factors. These different polarization states have distinct functions in ischemic stroke.
Signaling Pathways Involved in Microglial Activation in Ischemic Stroke
Multiple signaling pathways are involved in the transition between different microglial activation states. One such pathway is the signal transducer and activator of transcription 3 (STAT3) signaling pathway. STAT3 is a potential negative regulator of inflammatory cytokine release, and its phosphorylation is associated with microglial polarization. STAT3 is activated through tyrosine residue (Tyr705) and serine (Ser727) phosphorylation. The activation of STAT3 can promote both proinflammatory and anti-inflammatory microglial polarization. For example, in BV-2 cells treated with panaxatriol saponins, STAT3 activation was associated with M2 polarization, while inhibition of STAT3 activation reversed the anti-inflammatory effects. Conversely, in some cases, STAT3 activation may promote M1 polarization, as seen in oxygen-glucose deprivation (OGD) models where M2 polarization was inhibited.
Another important pathway is the STAT6 signaling pathway, which is significant for M2 microglial polarization. STAT6 activation facilitates efferocytosis, a process essential for microglia-induced neuroprotection. STAT6 knockout increases the number of proinflammatory microglia and reduces the phagocytosis of dead or dying neurons. Arginase 1 (Arg1), known to protect against neuroinflammation in the ischemic brain, is a target of STAT6. STAT6 activation results in decreased expression of Arg1 and dysfunctional phagocytosis.
The Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-kB)/mitogen-activated protein kinase (MAPK) signaling pathway is responsible for M1 microglial polarization. Activation of TLR4 recruits the adaptor protein myeloid differentiation factor 88 (MyD88), leading to the activation of downstream NF-kB and MAPK cascades. In a middle cerebral artery occlusion (MCAO) and reperfusion rat model, the increased levels of the p65 subunit of NF-kB and its inhibitor IkB were significantly reduced, exerting an anti-inflammatory effect through the TLR4/NF-kB signaling pathway.
The interferon regulatory factor 5 (IRF5)-IRF4 signaling pathway is also crucial in neuroinflammatory responses. Overexpression of IRF5 leads to a proinflammatory microglial response, while overexpression of IRF4 correlates with anti-inflammatory microglial activation. The expression of IRF5 and IRF4 has an inhibitory effect on each other, and their expression patterns correlate with the time course of brain microglial cytokine production after stroke.
Therapeutic Interventions to Modulate Microglial Polarization States in Ischemic Stroke
The transition from proinflammatory M1 microglia to anti-inflammatory M2 microglia is a promising therapeutic approach for ischemic stroke. Bendavia, a mitochondria-targeting tetrapeptide, reduces mitochondrial reactive oxygen species (ROS) and inhibits apoptosis. In a transient MCAO mouse model, Bendavia exerted antioxidative and anti-inflammatory effects, reducing matrix metalloproteinase-9 (MMP-9) and tumor necrosis factor-alpha (TNF-a) protein expression levels, and decreasing inflammatory microglia/macrophage activation.
Schisandrin B, a natural compound, mitigated the increased levels of TNF-a, IL-6, and IL-1b in MCAO and reperfusion rat models. Betaine, also known as N-trimethylglycine, exerts anti-inflammatory and neuroprotective effects by shifting the microglial polarization state from M1 to M2 in LPS-treated microglial cells. Betaine also reduces the expression of inducible nitric oxide synthase (iNOS) and CD16/32 while increasing the expression of CD206 and Arg1.
These therapeutic interventions aim to either inhibit the M1 polarization state or promote the M2 polarization state of microglia. The transition from M1 to M2 microglia reduces the release of proinflammatory cytokines and facilitates the phagocytosis of damaged cell debris, leading to improved neuronal protection and better prognosis for ischemic stroke patients.
Future Perspectives
Microglial polarization has been extensively investigated over the past few years and plays a critical role in ischemic stroke. Manipulating the polarization of microglia is a potential therapeutic strategy for ischemic stroke patients. However, further fundamental research and additional clinical trials are required to fully understand the underlying mechanisms of microglial polarization in ischemic stroke. Targeting microglial polarization provides a new avenue for the treatment of ischemic stroke and may also be a potential strategy for treating other neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.
doi.org/10.1097/CM9.0000000000001711
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