The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery

Abstract

Stroke causes varying degrees of neurological deficits, leading to corresponding dysfunctions. There are different therapeutic principles for each stage of pathological development. Neuroprotection is the main treatment in the acute phase, and functional recovery becomes primary in the subacute and chronic phases. Neuroplasticity is considered the basis of functional restoration and neurological rehabilitation after stroke, including the remodeling of dendrites and dendritic spines, axonal sprouting, myelin regeneration, synapse shaping, and neurogenesis. Spatiotemporal development affects the spontaneous rewiring of neural circuits and brain networks. Microglia are resident immune cells in the brain that contribute to homeostasis under physiological conditions. Microglia are activated immediately after stroke, and phenotypic polarization changes and phagocytic function are crucial for regulating focal and global brain inflammation and neurological recovery. We have previously shown that the development of neuroplasticity is spatiotemporally consistent with microglial activation, suggesting that microglia may have a profound impact on neuroplasticity after stroke and may be a key therapeutic target for post-stroke rehabilitation. In this review, we explore the impact of neuroplasticity on post-stroke restoration as well as the functions and mechanisms of microglial activation, polarization, and phagocytosis. This is followed by a summary of microglia-targeted rehabilitative interventions that influence neuroplasticity and promote stroke recovery.

Keywords: microglia; microglial phagocytosis; neuromodulation; neuroplasticity; rehabilitation; stroke.

Figure 1

Microglial activation and polarization affect neuroplasticity and functional recovery. Under pathological conditions, microglia can be activated by specific cytokines that upregulate transcription factors of downstream signaling pathways, thereby resulting in pro-inflammatory and anti-inflammatory phenotypic polarization. Non-coding RNA (ncRNA) expression also contributes to direct microglial polarization. Pro-inflammatory microglia tend to release pro-inflammatory factors and toxic molecules, which leads to increased neurotoxicity, neurological deficits, and tissue damage, ultimately leading to attenuated neuroplasticity and functional recovery. Conversely, anti-inflammatory microglia release anti-inflammatory factors and neurotrophins, resulting in increased neurotrophy and neuroprotection, thereby enhancing neuroplasticity and functional recovery. LPS, lipopolysaccharide; IFN-γ, interferon-γ; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-4, interleukin-4; IL-10, interleukin-10; IL-13, interleukin-13; STAT1, signal transducer and activator of transcription 1; STAT3, signal transducer and activator of transcription 3; IRF5, interferon regulatory factor 5; PPARγ, peroxisome proliferator-activated receptor γ; STAT6, signal transducer and activator of transcription 6; Nrf2, nuclear factor erythroid 2-related factor 2 ; IRF4, interferon regulatory factor 4; IL-6, interleukin-6; IL-12, interleukin-12; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase; MMP3, matrix metalloproteinase 3; MMP9, matrix metalloproteinase 9; TGF-β, transforming growth factor-β; IGF-1, insulin-like growth factor-1; CSF-1, colony-stimulating factor-1; VEGF, vascular endothelial growth factor; BDNF, brain-derived neurotrophic factor; GDNF, glial cell line-derived neurotrophic factor; Meg3, maternally expressed gene 3; Usp10, ubiquitin specific peptidase 10. Created with BioRender.com (accessed on 1 March 2023.

Figure 2

Surface receptors and the signaling pathways associated with microglia activation following stroke. After binding to endogenous ligand, TLR4 and IL-1R activate the MyD88/ NF-κB pathway to increase the release of pro-inflammatory cytokines and induce a pro-inflammatory response. S1PR2 and S1PR3 affect microglial M1 polarization through the ERK1/2 and JNK pathways and p38 MAPK pathway, respectively. TREM1 can activate the downstream CARD9/NF-κB and NLRP3/Caspase-1 signaling pathway to promote the release of inflammatory factors. TREM2- DAP12 interaction activates the PI3K/AKT signaling pathway, which can inhibit TLR4 signaling by blocking MAPK cascade. CB2R exerts anti-inflammatory effects after stroke. This mechanism may be related to inhibition of the TLR4/NF-κB signaling pathway. TLR4, toll-like receptor 4; IL-1R, interleukin-1 receptor; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor kappa-B; S1PR2, sphingosine-1-phosphate receptor 2; S1PR3, sphingosine-1-phosphate receptor 3; ERK1/2, extracellular signal-regulated kinases 1/2; JNK, c-Jun N-terminal kinase; p38 MAPK, p38 mitogen-activated protein kinase; TREM1, triggering receptor expressed on myeloid cells 1; CARD9, caspase recruitment domain family member 9; NLRP3, NOD-like receptor thermal protein domain associated protein 3; TREM2, triggering receptor expressed on myeloid cells 2; DAP12, DNAX activation protein 12; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; MAPK, mitogen-activated protein kinase; MKK3/6, mitogen-activated protein kinase kinase 3/6; MKK4/7, mitogen-activated protein kinase kinase 4/7; MEK1/2, mitogen-activated protein kinase kinase 1/2; SYK, spleen tyrosine kinase; TRAF6, tumor necrosis factor receptor-associated factor 6; IL-1β, interleukin-1β; IL-18, interleukin-18; GSDMD, Gasdermin D. Created with BioRender.com.

Figure 3

After stroke, activated microglia mediate phagocytosis in the central nervous system through a combination of ligands expressed by target cells and corresponding receptors in microglia. After stroke, activated microglia can directly phagocytose damaged or dead neurons (a), cell debris (b), myelin debris (c), and peripheral neutrophils (d) to reduce inflammatory responses, create a microenvironment for tissue repair, and restore brain homeostasis. Microglia can also phagocytose vascular endothelial cells and astrocytic endfeet (e) to damage the integrity of the blood-brain barrier and exacerbate the inflammatory development. In addition, neuronal exosomes and microglial exosomes can promote synaptic pruning (f). (a) Injured neurons can express “Find me” signals, including CX3CL, ATP, UTP, and UDP, recognized by corresponding microglial receptors including CX3CR, P2Y12R, P2Y6R, and “eat me” signals including PS, calreticulin, C3 recognized by LRP, MerTK, and C3R respectively. “Do not eat me” signal (CD47) can be downregulated, and its receptor is SIRPα. (d) Neutrophils release CSF-1, which is recognized by CSF-1R in microglia. (e) Vascular endothelial cells secrete CCL5, which binds to CCR5 in microglia to play a protective role in maintaining the integrity of the blood-brain barrier. Other microglial surface receptors, including TREM2, SR-A, SR-BI, CD36, are involved in the clearance of apoptotic cells as well as cell and myelin debris. CX3CL, C-X3-C motif chemokine ligand; CX3CR, C-X3-C motif chemokine receptor; ATP, adenosine triphosphate; UTP, uridine triphosphate; UDP, uridine diphosphate; P2Y12R, P2Y12 receptor; P2Y6R, P2Y6 receptor; PS, phosphatidylserine; MerTK, c-mer tyrosine kinase; C3, complement 3; C3R, C3 receptor; LRP, low-density lipoprotein receptor-associated protein; SIRPα, signal regulatory protein α; CSF-1, colony-stimulating factor-1; CSF-1R, CSF-1 receptor; CCL5, C-C motif chemokine ligand 5; CCR5, C-C motif chemokine receptor 5; TREM2, triggering receptor expressed on myeloid cells 2; DAP12, DNAX activation protein 12; SR-A, scavenger receptor A; SR-BI, scavenger receptor class B type I. Created with BioRender.com.