Review of Front Aging Neurosci︱Astrocytes in the neurovascular unit after cerebral ischemia

Written by ︱Han Guangyuan, edited by Song Lijuan ︱Wang SizhenIschemic stroke is a disorder of blood supply to the brain caused by various cerebrovascular diseases, resulting in ischemia and hypoxic necrosis of local brain tissue, and corresponding neurological functions appear rapidly A class of clinical syndromes with defects [1]
.

Globally, ischemic stroke accounts for about 87% of stroke patients and continues to rise [2]
.

At present, the treatment of ischemic stroke mainly focuses on thrombolysis, thrombectomy and neuroprotection, but none of them have achieved satisfactory results
.

More and more studies have shown that neurons, astrocytes (Ast), and blood brain barrier (BBB) ​​are all damaged to varying degrees after ischemic stroke, indicating that targeting Neuron or single cell therapy for ischemic stroke may not be promising
.

American scientist Lo et al.
proposed the concept of neurovascular unit (NVU) in 2003, which brought new ideas for the discussion of the pathogenesis of ischemic stroke, drug therapy targets, and diagnosis and treatment strategies [3]
.

 NVU is composed of neurons, Ast, microglia (MG), BBB and extracellular matrix (ECM), and plays a role in the maintenance of normal brain function and the treatment of various brain diseases including ischemic stroke important
.

Ast is the most numerous cell in the brain and plays a role in nourishment, support and protection
.

After ischemic stroke, Ast participates in the complex dual role of protecting and injuring brain tissue through multiple signaling pathways in NVU
.

Therefore, an in-depth understanding of the role of Ast in ischemic stroke NVU and its pathological process is of great significance for the treatment of ischemic stroke
.

 On April 7, 2022, the team of Professor Ma Cungen from the Neurobiology Research Center of Shanxi University of Traditional Chinese Medicine/Key Laboratory of Multiple Sclerosis, Qi and Activating Blood circulation of the State Administration of Traditional Chinese Medicine presented a presentation on Frontiers in Aging Neuroscience.
A recent review article titled "The Important Double-Edged Role of Astrocytes in Neurovascular Unit After Ischemic Stroke" was published, clarifying the double-edged role of Ast in NVU after cerebral ischemia
.

Master Han Guangyuan and Associate Professor Song Lijuan are the co-first authors of the article, and Professor Yan Yuqing, Director Huang Jianjun and Professor Ma Cungen are the corresponding authors
.

The author specifically described the function of Ast in NVU, emphasized the double-edged sword role of Ast in NVU after cerebral ischemia, and discussed the related drugs and mechanisms of targeting Ast in the treatment of cerebral ischemia.
Detailed list statement
.

On this basis, the prospect of Ast as a regulatory target of NVU is made, which provides a new idea for the prevention and treatment of ischemic stroke
.

 Research progress 1.
Function of Ast in NVU 2.
Ast and MG: MG and Ast are usually activated into two states: neurotoxin phenotype (M1/A1) and neuroprotective phenotype (M2/A2), corresponding to Injury or repair function in NVU [7]
.

Activated MG induces A1-like Ast formation by secreting IL-1α, TNF, and C1q, which loses its ability to promote neuronal survival, growth, synapse formation, and phagocytosis, resulting in neuronal and oligodendrocyte death [8]
.

MG and Ast can also interact in a paracrine manner, and their effects may be affected by TGF-β, IL-1, ATP, etc.
[9]
.

In addition, there may be a specific pyrimidine receptor-related pathway between MG and Ast, which may affect chronic inflammation in neurons and reactive glial cells [10]
.

Figure 1 The interaction between Ast and MG in the inflammatory response of cerebral ischemia (Source: Han Guangyuan et al.
, Chinese Journal of Immunology, 2022) 3.
Ast and BBB: BBB is composed of brain endothelial cells, pericytes, ECM basal layer and A dynamic complex composed of Ast terminals [11]
.

Ast interacts with cerebral microvascular endothelial cells to jointly induce the formation of BBB and maintain the integrity of BBB [12]
.

Pericytes, as integrators, coordinators, and effectors of neurovascular functions, are a very important component of NVU, regulating BBB integrity [13], regulating cerebral blood flow [14], and clearing and phagocytizing cell debris [15] , its function may be closely related to Ast can affect calcium ion concentration [16]
.

 4.
Ast and ECM: ECM is secreted by neurons or glial cells, surrounds the dynamic structure of cells, provides support for cell arrangement, and performs a series of physiological functions [17]
.

Overexpression of MMP-2 and MMP-9 in Ast after ischemic stroke can disrupt the structure of the ECM and increase the permeability of the BBB [18]
.

In addition, certain cytokines secreted by Ast can cause changes in the composition and structural integrity of the ECM [19]; ​​in turn, disruption of the ECM can significantly alter the function of Ast
.

Figure 2 Schematic diagram of neurovascular unit (Source: Han GY, et al.
, Front Aging Neurosci, 2022) 2.
The double-edged role of Ast in NVU after cerebral ischemia Under normal physiological conditions, low levels of Ast are more secreted Neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF)
.

In ischemic state, Ast is activated, its morphology changes, and the marker proteins GFAP and vimentin increase [20]
.

Ast has a strong tolerance to ischemia.
On the one hand, it protects neurons by releasing neurotrophic factors, ingesting excitatory amino acids, anti-inflammatory and antioxidant.
On the other hand, it can also produce excitatory amino acids, The release of inflammatory mediators and other pathways damage neurons
.

Therefore, Ast is a double-edged sword in the pathological process of cerebral ischemia
.

It has both neurotoxic and neuroprotective effects on the CNS
.

 (1) Protective effect 1.
Release of neurotrophic factor: Ast is the main source of neurotrophic factor in CNS
.

After cerebral ischemia, A1 and A2 reactive ast (reactive astrocytes, RAs) can secrete a variety of trophic factors, including bFGF, BDNF, GDNF [21], erythropoietin (EPO) [22], neurotrophic factor -3 (NT3) [23], etc.
, these trophic factors can promote the regeneration of axons and blood vessels, the formation of myelin sheath and synaptic plasticity
.

 2.
Uptake of excitatory amino acids: After cerebral ischemia, a large amount of glutamate is released into the intercellular space to induce excitotoxicity, which is one of the main mechanisms leading to neuronal death during cerebral ischemia
.

However, Ast can uptake excess glutamate in the synaptic cleft through glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST), which plays a neuroprotective role [24]
.

 3.
Anti-inflammatory and antioxidant: Cerebral ischemia can cause a series of inflammatory reactions, and Ast has a certain anti-inflammatory effect to protect the CNS
.

At the peak of inflammation, Ast inhibits the inflammatory response by regulating the secretion of anti-inflammatory cytokines such as TGF-β and IL-10 [25]
.

Secondly, Ast can inhibit the inflammatory response mediated by MG, limit the infiltration of peripheral inflammatory cells and some bacteria through the BBB, repair the damaged BBB, and enhance the phagocytic ability of neutrophils to inhibit inflammation [26]
.

In addition, Ast can also exert a strong antioxidant capacity
.

First, Ast can produce insulin-like growth factor I, activate protein kinase B [27], express connexin 43 (Cx43), and form gap junctions to exert antioxidant effects and secrete G protein-coupled receptor GPR37-like 1 (GPR37L1) for protection Ast is protected from oxidative stress damage [28]
.

Second, Ast can promote NF-E2-related factor 2 (Nrf2) to enter the nucleus and bind to antioxidant response elements (AREs), protecting Ast and adjacent neurons from oxidative damage [29]
.

 4.
Formation of glial scars: After cerebral ischemia, the inflammatory response in the brain promotes the activation of Ast, and the RAs around the infarct area secrete ECM components, which together with MG form glial scars [30]
.

This molecular barrier can effectively separate the damaged area from normal tissue, inhibit the diffusion of toxic substances, and reduce neuronal death caused by excitatory amino acids and neurotoxic substances [31]
.

 (II) Injury effect 1.
Release of neurotoxic substances and pro-inflammatory cytokines: In ischemic state, Ast can secrete a large number of inflammatory factors such as TNF-α, IL-1β, aggravate the degree of cerebral edema, and participate in inflammatory reactions [32]
.

These inflammatory mediators can further stimulate the activation and proliferation of glial cells, thereby intensifying the inflammatory response and forming a vicious circle
.

At the same time, in this process, TNF-α can induce the release of neurotoxic substances such as glutamate and nitric oxide, aggravating the inflammatory response
.

 2.
Ast and matrix metalloproteinases (MMPs): After cerebral ischemia, MMPs can not only degrade the ECM, but also destroy the integrity of the BBB
.

Studies have confirmed that there is a certain relationship between acute ischemic stroke and MMPs
.

Figure 3 The dual role of Ast in NVU (Source: Han GY, et al.
, Front Aging Neurosci, 2022) 3.
Targeting Ast to treat cerebral ischemia Ast participates in ischemic stroke by activating or inhibiting multiple signaling pathways The pathological process plays a complex dual role on neurons
.

Studies have found that a variety of drugs can target Ast to play a protective role and reduce CNS damage
.

The authors listed a variety of drugs targeting Ast via ERK1/2, TLR4/NF-κB and other related pathways to treat or prevent ischemic stroke
.

Figure 3.
Drugs targeting Ast in the treatment of cerebral ischemia (source: Han GY, et al.
, Front Aging Neurosci, 2022) Summary and outlook Glial cells are closely related and play a crucial role as a double-edged sword
.

On the one hand, it protects brain tissue by anti-inflammatory, antioxidant and release of neurotrophic factors; on the other hand, it releases neurotoxic substances, destroys the BBB and promotes brain damage
.

A variety of signaling pathways form a complex network of signaling molecules in NVU, in which Ast participates and plays an important regulatory role
.

At present, the treatment of ischemic stroke still needs to be explored and improved, and the interaction between signaling molecules needs to be further elucidated
.

Although a variety of drugs have shown the potential of targeting Ast to play a certain and positive role in recovery after ischemic stroke, most of them are still in basic research due to the complexity and diversity of the underlying mechanisms.
Or in phase I and II clinical trials, there is still a long way to go before clinical application
.

Focusing on the double-edged role of Ast in NVU after cerebral ischemia, how to seek advantages and avoid disadvantages, that is, to promote the protective effect of Ast and inhibit its damage effect will become a hotspot for further research
.

It is believed that targeting Ast in the treatment of ischemic stroke may play a key role in the future
.

 Original link: https://doi.
org/10.
3389/fnagi.
2022.
833431 First author: Master Han Guangyuan (first from left), Associate Professor Song Lijuan (second from left); Corresponding authors: Professor Yan Yuqing (middle), Director Huang Jianjun (second from right), Professor Ma Cungen (the first from the right) (Photo courtesy of: Neurobiology Research Center of Shanxi University of Traditional Chinese Medicine/Key Laboratory of Multiple Sclerosis, Qi and Activating Blood, State Administration of Traditional Chinese Medicine) Fund support: National Natural Science Foundation of China (82004028, 81473577), China Postdoctoral Science Foundation Project (2020M680912), Shanxi Province Applied Basic Research Project (201803D421073, 201805D111009, 201901D211538)
.

Brief introduction of laboratory and corresponding author (scroll up and down to read) Neurobiology Research Center of Shanxi University of Traditional Chinese Medicine/Key Laboratory of Multiple Sclerosis, Qi and Activation of Blood of State Administration of Traditional Chinese Medicine is a key subject of State Administration of Traditional Chinese Medicine
.

After years of construction, the discipline has gradually condensed and formed four stable research directions, namely, the role of integrated traditional Chinese and Western medicine in preventing and treating ischemic cerebrovascular disease and its mechanism, and the role of integrated traditional Chinese and Western medicine in preventing and treating multiple sclerosis and other demyelinating diseases.
Research on its mechanism, research on the effect and mechanism of integrated traditional Chinese and western medicine in preventing and treating Alzheimer's disease and vascular dementia, and research on the effect and mechanism of integrated traditional Chinese and western medicine in preventing and treating Parkinson's disease and other movement disorders
.

These four directions are characterized by the prevention and treatment of the above-mentioned diseases by the TCM theory of nourishing qi and activating blood.
The research advantage of intervention based on the theory of "same treatment for different diseases"
.

 Ma Cungen, director of the department center/research office, second-level professor, doctoral supervisor, subject leader, member of the Chinese Medicine Teaching Steering Committee of the Ministry of Education; Zhongjing Inheritance and Innovation Professional Committee of the World Federation of Chinese Medicine Societies / Zhongjing of the Chinese Association of Chinese Medicine Vice Chairman of Academic Inheritance and Innovation Community
.

The research direction is the prevention and treatment of central nervous system diseases with integrated traditional Chinese and Western medicine
.

He has published more than 260 academic papers, of which more than 60 are included in SCI journals, and have been positively cited hundreds of times by journals such as Immunol Res and Glia
.

Talent recruitment[1] "Logical Neuroscience" is looking for associate editor/editor/operation position (online office) Selected articles from previous issues[1] J Neuroinflammation︱Peng Ying's research group reveals that mitophagy in microglia is induced by morphine The regulatory role of inflammatory inhibition in the central nervous system [2] Curr Biol︱ Novelty detection and the relationship between surprise and recency in the primate brain [3] Neurosci Bull︱ Qian Lingjia's group reveals that homocysteine ​​plays a role in chronic Influence of cognitive function by regulating DNA methylation during stress【4】Front Aging Neurosci︱Ma Tao’s team revealed the mechanism of Chinese herbal compound multi-pathway and multi-target improving energy metabolism in Alzheimer’s disease【5】Aging Cell︱ Gao Xu's team found that good sleep quality can delay the accelerated aging caused by air pollution [6] Autophagy︱ Shen Hanming's group revealed a new mechanism of autophagy-related protein WIPI2 regulating mitochondrial outer membrane protein degradation and mitophagy [7] Neuron heavy review ︱ Sheng Zuhang’s team focused on the important role of axonal mitochondria maintenance and energy supply in neurodegenerative diseases and post-neural repair [8] Cell Death Dis︱ Kong Hui et al.
revealed that the P2X7/NLRP3 inflammasome pathway plays an important role in early diabetic retinopathy 【9】Sci Adv︱Liu Xingguo/Tian Mei's team discovered a new mechanism of mitochondrial clearance in drug-induced Parkinson's syndrome【10】Front Aging Neurosci︱Gut preparation can affect postoperative delirium by changing the composition of microflora Course recommendation [1] Symposium on Patch Clamp and Optogenetics and Calcium Imaging Technology Tencent Conference on May 14-15 [2] Scientific Research Skills︱ The 4th NIR Brain Function Data Analysis Class (Online: 2022.
4.
18~4.
30 ) References (swipe up and down to read) 1.
Zhao Y, Yang JH, Li C, et al.
Role of the neurovascular unit in the process of cerebral ischemic injury.
Pharmacol Res, 2020, 160:1051032.
Saini V, Guada L, Yavagal DR.
Global epidemiology of stroke and access to acute aschemic atroke interventions.
Neurology.
2021, 97(20 Suppl 2):S6-S16.
3.
Lo EH, Dalkara T, Moskowitz MA.
Mechanisms, challenges and opportunities in stroke.
Nat Rev Neurosci.
2003, 4(5):399-415.
4.
Naranjo O, Osborne O, Torices S, et al.
In vivo targeting of the neurovascular unit: challenges and advancements.
Cell Mol Neurobiol.
2021.
5.
Lo EH.
Degeneration and repair in central nervous system disease[J].
Nat Med, 2010, 16(11):1205-1209.
6.
Stogsdill JA, Ramirez J, Liu D, et al.
Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis.
Nature.
2017, 551(7679):192 -197.
7.
Liu LR, Liu JC, Bao JS, et al.
Interaction of microglia and astrocytes in the neurovascular unit.
Front Immunol.
2020, 11:1024.
8.
Liddelow SA, Guttenplan KA, Clarke LE, et al.
Neurotoxic reactive astrocytes are induced by activated microglia.
Nature, 2017, 541(7638):481-487.
9.
Liu W, Tang Y, Feng J.
Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system.
Life Sci , 2011, 89(5-6): 141-146.
10.
Quintas C, Pinho D, Pereira C, et al.
Microglia P2Y6 receptors mediate nitric oxide release and astrocyte apoptosis.
J Neuroinflamm, 2014, 11(1):1-12.
11 .
Najjar S, Pearlman DM, Devinsky O, et al.
Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence.
J Neuroinflammation, 2013, 10:142.
12.
Thurgur H, Pinteaux E .
Microglia in the neurovascular unit: blood–brain barrier–microglia interactions after central nervous system disorders.
Neuroscience, 2019, 405:55–6713.
Zheng ZT, Chopp M, Chen JL.
Multifaceted roles of pericytes in central nervous system homeostasis and disease.
J Cereb Blood Flow Metab.
2020, 40(7):1381-1401.
14.
Kisler K, Nelson AR, Montagne A, et al.
Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease.
Nat Rev Neurosci.
2017,18:419-434.
15.
Sá-Pereira I, Brites D, Brito MA.
Neurovascular unit: a focus on pericytes.
Mol Neurobiol, 2012, 45(2 ): 327-347.
16.
Iadecola C.
The neurovascular unit coming of age: A journey through neurovascular coupling in health and disease.
Neuron.
2017, 96(1):17-42.
17.
De Luca C, Colangelo AM, Virtuoso A, et al.
Neurons, glia, extracellular matrix and neurovascular unit: A systems biology approach to the complexity of synaptic plasticity in health and disease.
Int J Mol Sci.
2020, 21(4):153918.
Keep Richard F, Zhou NN, Xiang JM , et al.
Vascular disruption and blood-brain barrier dysfunction in intracerebral hemorrhage.
Fluids and Barriers of the CNS, 2014, 11:18.
19.
De Luca C, Colangelo AM, Alberghina L, et al.
Neuro-immune hemostasis: Homeostasis and diseases in the central nervous system.
Front Cell Neurosci, 2018, 12, 459.
20.
Pekny M, Wilhelmsson U, Tatlisumak T, et al.
Astrocyte activation and reactive gliosis-A new target in stroke? Neurosci Lett.
2019 Jan 10;689:45-55.
21.
Liu Z, Chopp M.
Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke.
Prog Neurobiol, 2016, 144: 103-120.
22.
Roe C.
Unwrapping Neurotrophic Cytokines and Histone Modification.
Cell Mol Neurobiol.
2017 Jan;37(1): 1-4.
23.
Jurič DM, Mele T, Carman-Kržan M.
Involvement of histaminergic receptor mechanisms in the stimulation of NT-3 synthesis in astrocytes.
Neuropharmacology.
2011 Jun;60(7-8):1309-17.
24.
Racalixtoa B, Donag C, Mez GP.
The role of astrocytes in neuroprotection after brain stroke: potential in cell therapy.
Front Mol Neurosci, 2017, 10( 159) : 8825.
Norden DM, Fenn AM, Dugan A, et al.
TGFβ produced by IL-10 redirected astrocytes attenuates microglial activation.
Glia, 2014, 62(6):881-95.
26.
Xie L, Poteet EC, Li W , et al.
Modulation of polymorphonuclear neutrophil functions by astrocytes.
J Neuroinflammation.
2010, 7:53.
27.
Davila D, Fernandez S, Torres-Aleman I.
Astrocyte resilience to oxidative stress induced by insulin-like growth factor I (IGF-I) involves preserved AKT (protein kinase B) activity.
J Biol Chem, 2016, 291(5): 2510-2523.
28.
Jolly S, Bazargani N, Quiroga AC, et al.
G protein-coupled receptor 37-like 1 modulates astrocyte glutamate transporters and neuronal NMDA receptors and is neuroprotective in ischemia.
Glia, 2018, 66(1): 47-61.
29.
Zhou Y, Duan S, Zhou Y, et al.
Sulfiredoxin- 1 attenuates oxidative stress via Nrf2/ARE pathway and 2-Cys Prdxs after oxygen-glucose deprivation in astrocytes.
J Mol Neurosci, 2015, 55(4): 941-950.
30.
Huang L, Wu ZB, Zhuge Q, et al.
Glial Scar formation occurs in the human brain after ischemic stroke.
Int J Med Sci, 2014, 11(4): 344-348.
31.
Sato Y, Nakanishi K, Tokita Y, et al.
A highly sulfated chondroitin sulfate preparation, CS- E, prevents excitatory amino acid-induced neuronal cell death.
J Neurochem, 2008, 104(6):1565-1576.
32.
Xin WQ, Wei W, Pan YL, et al.
Modulating poststroke inflammatory mechanisms: Novel aspects of mesenchymal stem cells,extracellular vesicles and microglia.
World Journal of Stem Cells, 2021, 13(08):1030-1048.
Plate making︱Sizhen Wang End of this article