The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery
Abstract
:1. Introduction
2. Pathophysiology and Therapeutic Target of Stroke Recovery
2.1. Pathophysiology of Stroke in Different Phases
2.2. The Basis of Functional Recovery: Neuroplasticity
2.2.1. Remodeling of Dendrites and Dendritic Spines
2.2.2. Axonal Sprouting
2.2.3. Myelin Regeneration
2.2.4. Neurogenesis
3. Activation and Polarization of Microglia following Stroke
3.1. Microglia in CNS
3.2. Spatiotemporal Distribution of Microglia and Colocalization between Microglia Activation and Neuroplasticity after Stroke
3.3. Molecular Mechanism of Microglial Activation and Polarization Following Stroke
3.3.1. Surface Receptor
3.3.2. Transcription Factor
3.3.3. Non-Coding RNA
4. Microglia Phagocytic Function following Stroke
4.1. Microglia Phagocytotic Function during Physiological State
4.2. Functional Changes of Microglia Phagocytosis after Stroke
4.3. Phagocytic Signaling
4.3.1. Find Me Signal
4.3.2. Eat Me Signal
4.3.3. Do Not Eat Me Signal
5. Therapeutic Intervention Targeting Microglia in Stroke Rehabilitation
5.1. Pharmacotherapy
Drug | In Vivo | In Vitro | Effect on Microglia | Signal | Reference | ||
---|---|---|---|---|---|---|---|
Animal Model | Treatment | Cell Culture | Treatment | ||||
Minocycline | Mouse (tMCAO) | Intraperitoneal injections after MCAO induction; 10, 25, and 50 mg/kg/day for 3 consecutive days | BV2 microglial cells oxygen–glucose deprivation/reoxygenation (OGD/R) cell model | Minocycline at doses of 0.01, 0.1, 1, 10, and 100 μM; preincubated 1 h before OGD/R injury | IL-1β↓, IL-18↓, NLRP3↓ | [239] | |
Rats (tMCAO) | Intravenous injection after reperfusion onset; a single dose (3 mg/kg) | IL-1β↓, TNF-α↓, IL-10↑, TGF-β↑, Ym1↑ | [240] | ||||
Mouse (MCAO/R) | Intraperitoneal injections after reperfusion; 10, 25, or 50 mg/kg/day for 2 weeks | Primary microglia from cerebral cortex of newborn mice | LPS (100 ng/mL) + IFN-γ (20 ng/mL) + minocycline (50 μM); incubation for 24 h | IL-1β↓, IL-6↓, iNOS↓, TNF-α↓, Arg-1↑, IL-10↑, TGF-β↑, Ym1↑ | STAT1/STAT6 pathways ↓ | [241] | |
Wnt-3a | Mouse (tMCAO) | Intranasally delivered at the time of reperfusion and next 2 days; 2 μg/kg/day | iNOS↓, TNF-α↓, Arg-1↑, CD206 ↑ | [242] | |||
Gal-3 | Mouse (MCAO) | Intracortical injection at 24 h following MCAO; 100 ng/mouse (20–25 g) | Primary cell cultures from the brains of the adult, 8–9-week-old C57BL/6 wild-type mice | Incubation with Gal-3 (5 μM) for 24 h | TNF-α↓, IL-1β↓, IFN-γ↓, IL-17↓, iNOS↓, Ym1↑, IL-4 ↑, IL-6 ↑ | [243] | |
Atorvastatin | Mouse (pMCAO) | Oral gavage after MCAO induction; 20 mg/kg/day | IL-6↓, TNF-α↓, MCP-1↓, IL-10 ↑ | [244] | |||
Exendin-4 | Mouse (MCAO) | Intraperitoneal injection; 50 mg/kg at 1.5 h after MCAO induction; 0.2 mg/kg daily for 3 days until sacrifice | Primary microglia-enriched cultures were prepared from whole brains of 2- to 3- day-old mice | LPS (10 ng/mL) + Ex-4 (40 ng/mL); incubation for 24 h | CD206↑, Arg-1↑, Ym1/2↑ | [245] | |
Bendavia | Mouse (tMCAO) | Intraperitoneal injection immediately after reperfusion and 4 h later; 5 mg/kg | MMP9↓, TNF-α ↓ | [246] | |||
Vx-765 | Mouse (MCAO) | intraperitoneal injection starting immediately after MCAO induction; 50 mg/kg for 3 consecutive days | IL-1β↓, TNF-α↓, iNOS↓, TGF-β↑, Ym1↑ | NF-κB signaling↓ | [247] | ||
Baicalein | Mouse (MCAO) | Intragastrical administration after reperfusion; 100 mg/kg/day for 3 days | BV2 microglial cells |
| Ym1/2↑, Arg-1↑, CD206↑, TNF-α↓, IL-1β↓, IL-6↓, NO↓ | TLR4/NF-κB ↓, phosphorylated STAT1 ↓ | [248] |
Cottonseed oil | Rats (MCAO/R) | Subcutaneous injection before MCAO; 1.3 mL/kg/day for 3 weeks | IL-1β↓, IL-6↓, TNF-α↓ | TLR4/NF-κB ↓ | [249] | ||
GJ-4 | Rats (MCAO/R) | Oral administration after MCAO induction; 10, 25, 50 mg/kg/day for 12 days | iNOS↓, COX-2↓, MMP9↓ | JAK2/STAT1 ↓ | [251] | ||
Melatonin | Mouse (dMCAO) | 20 mg/kg at 0 and 24 h after reperfusion | Co-culture of BV2 cells (growing on culture inserts) and OGD neuron | Melatonin (100, 200, or 400 mM); incubation for 12 h | pro-inflammatory markers ↓, anti-inflammatory markers ↑ | p-STAT3/STAT3↑ | [252] |
Ki20227 | Mouse (PT) | Oral gavage before modeling; 0.002 mg/kg/day for 7 consecutive days | TNF-α↓, iNOS ↓, IL-10↑, Arg-1 ↑, NLRP3↓, Active caspase 1 ↓ | NF-κB signaling↓ | [253] | ||
Curcumin | Mouse (tMCAO) | Intraperitoneal injection; 150 mg/kg at 0 h and 24 h after reperfusion | BV2 microglial cells | LPS (100 ng/mL) + IFN-γ (20 ng/mL) + curcumin (12.5 and 25 µmol/L); incubation for 48 h | TNF-α↓, IL-12p70↓, IL-6 ↓ | [255] | |
Mouse (MCAO/R) | Intraperitoneal injection; 150 mg/kg/day for 7 days after ischemic stroke | Primary microglia were isolated from the whole brains of neonatal C57BL/6J mice | LPS (100 ng/mL) + curcumin (12.5 μM); incubation for 24 h | NLRP3/NF-κB pathway ↓ | [256] |
5.2. Exercise
Type | Treatment (Intensity, Time, Frequency, Duration) | Model | Effect on Microglia | Outcome | Reference | |
---|---|---|---|---|---|---|
Exercise | Treadmill exercise | 12 m/min; 30 min/day; 3 or 6 consecutive days | Rats (MCAO) | IL-4↑ M1-like markers↓ M2-like markers↑ | Improving neurobehavioral outcomes | [270] |
5–6 m/min; 5 min/day; 3 consecutive days | Mouse (MCAO) | NLRP3↓ | Showing better improvements at functional levels | [268] | ||
HIT program: 10 days (>25 m/min) MOD program: 2 days (<20 m/min) | Rats (MCAO) | IL-10↑, p75NTR↑, BDNF↑ | Promoting cerebral plasticity | [269] | ||
30 min/day; 5 days/week; 4 weeks | Mouse (MCAO) | Iba1+↑ (hippocampal CA1 region) | Alleviating increased neuroinflammation | [271] | ||
25 cm/s; 30 min/day; 3 days/week 4.5 weeks | Mouse (MCAO) | IL-10↑, NLRP3↑, IFN-γ↑, Gal-3↓ (caused by stress) | Having beneficial neuro-inflammatory effects; inducing detrimental stress response by forced running | [280] | ||
10 m/min; 60 min/day; 5 weeks | Mouse (microinjection of collagenase into the striatum region) | CD36/Iba1-double positive cells↑ | Contributing to neuroprotection | [278] | ||
12 m/min; 30 min/day; 5 times/week; 4 weeks | Rats (MCAO) (exosomes injection) | Excessive microglial activation↓, Syn↑, PSD-95↑ | Regulating synaptic plasticity and protecting neural function | [273] | ||
Skilled reaching training of the impaired forelimb | 5 days/week; 14 or 42 days | Rats (PT) | Excessive microglial activation↓ | Modulating perilesional cellular plasticity and contributing to a better functional recovery | [276] | |
10 or 42 days | Rats (PT) | Excessive microglial activation↓ | Improving functional recovery | [277] | ||
rTMS | Continuous TBS | 5 min (3 pulses of 50 Hz repeated every 200 ms); 5 days | Rats (PT) | Pro-inflammatory cytokines↓ | Improving the local neuronal microenvironment | [281] |
5 min (3 pulses of 50 Hz, repeated every 200 ms); 6 days | Rats (PT) | TGF-β↑, VEGF↑, HIF-1α↑ | Presenting protective effects in the context of ischemic stroke; contributing to vascular repair and protection | [282] | ||
Intermittent TBS | Ten 50 Hz bursts with 3 pulses each repeated 20 times at 5 Hz intervals; twice per day; 7 continuous days | Mouse (MCAO) | TLR4/NF-κB/NLRP3 signaling pathway↓ | Alleviating locomotor deficits and neuronal pyroptosis | [283] | |
High frequency | 10 Hz rTMS with a total of 60 trains; 20 pulses per train (1200 pulses); 10 s intertrain interval; for 11 min 44 s | Rats (MCAO) | NF-κB↓, STAT6↓ | Promoting neurogenesis and improving neural function recovery | [284] | |
tDCS | Cathodal | 500 µA, 15 min; once per day; 10 days | Rats (MCAO) | Iba1+↓ Pro-inflammatory factors↓ Anti-inflammatory factor↑ | Accelerating recovery from neurologic deficit and brain damage | [285] |
250 µA; 40 min; 1 day | Mouse (PT) | CD206↑ CD68↓ | Being effective from a functional point of view | [286] | ||
250 µA; 40 min | Mouse (MCAO) | Iba1+↓ GABA and glutamate↓ | Exerting a measurable neuroprotective effect | [287] | ||
Anodal | 250 µA; 15 min; 10 days | Mouse (MCAO) | Iba1+↓ | Inducing regeneration and promoting functional recovery | [288] | |
Cathodal or anodal | 250 µA (110.13 A/m2) or 500 µA (220.3 A/m2); 15 days | Mouse (PT) | CD16/32↓, Iba1+↓ | Impacting neurogenesis and influencing functional recovery | [289] | |
TUS/ tFUS | Low intensity | 528 mW/cm2; 5 days; 15 min/day; 5 days before MCAO | Mouse (MCAO) | VEGF↑, BDNF↑, Caspase-3↓ | Ameliorating brain damage | [290] |
86 mW/cm2; 60 min | Rats (dMCAO) | Inflammatory factors↓ | Increasing cerebral blood flow and supporting neuroprotection | [291] | ||
0.5 MHz; 120 mW/cm2; 7 consecutive days; | Mouse (MCAO) | M2 microglia↑ IL-10 and IL-10R↑ | Promoting neurorehabilitation | [292] |
5.3. Cell-Based Therapy
5.4. Noninvasive Brain Stimulation
6. Conclusions and Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Acute Phase of Stroke | Subacute Phase of Stroke | Chronic Phase of Stroke | |
---|---|---|---|
Time course | Minutes to days | Days to weeks | Weeks to mouths |
Pathophysiological mechanisms | Infiltration of peripheral immune cells; activation of resident glial cells; disturbance of ionic homeostasis; oxidative stress; BBB destruction; mitochondrial dysfunction; DNA damage | Amplification of immune responses; increased ROS production; cell edema and ion imbalances | Decrease in excitotoxicity; protective inflammatory response |
Axonal sprouting, dendrite remodeling; neurogenesis, angiogenesis; increased levels of growth factors | |||
Consequences | Cell injury or death | Onset of neuroplasticity | Tissue repair |
Therapeutic targets | Neuroprotection; reducing reperfusion injury | Functional rehabilitation |
Species | Model | Microglia Subset | Gene | Protocol | Reference |
---|---|---|---|---|---|
CD-1 mice | In embryonic development | The subsets during CNS development and homeostasis in the adult brain | Ctsb, Ctsd, Lamp1, Apoe, Tmsb4x, Eef1a1, Rpl4, Cst3 | SMART-seq2 | [101] |
In postnatal development | Tmem119, Selplg, Slc2a5, Malat1 | ||||
C57BL/6J mice | Aging brain (P540) | Aging clusters (OA) 2 | Lgals3, Cst7, chemokines Ccl4, Ccl3, Il1b, Id2, Atf3 | 10 × Genomics | [102] |
Aging clusters (OA) 3 | Ifitm3, Rtp4, Oasl2 | ||||
Heterozygous 5XFAD transgenic mice | AD | Microglia type associated with neurodegenerative diseases (DAM) | Apoe, Lpl, Cst7 ↑ P2ry12, Cx3cr1, Tmem119 ↓ | MARS-seq | [103] |
Frozen human post-mortem midbrain tissue sections | Idiopathic PD | Microglia cluster involving inflammatory response | IL1B, GPNMB, HSP90AA1 | 10 × Genomics | [104] |
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Qiao, C.; Liu, Z.; Qie, S. The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery. Biomolecules 2023, 13, 571. https://doi.org/10.3390/biom13030571
Qiao C, Liu Z, Qie S. The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery. Biomolecules. 2023; 13(3):571. https://doi.org/10.3390/biom13030571
Chicago/Turabian StyleQiao, Chenye, Zongjian Liu, and Shuyan Qie. 2023. "The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery" Biomolecules 13, no. 3: 571. https://doi.org/10.3390/biom13030571
APA StyleQiao, C., Liu, Z., & Qie, S. (2023). The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery. Biomolecules, 13(3), 571. https://doi.org/10.3390/biom13030571