The Role of CCL2/CCR2 Axis in Cerebral Ischemia-Reperfusion Injury and Treatment: From Animal Experiments to Clinical Trials
Abstract
:1. Introduction
2. CCL2 and CCR2 Signaling Pathway
3. Expression of CCL2/CCR2 in the Central Nervous System
4. CCL2/CCR2 Axis and Cerebral Ischemia-Reperfusion Injury and Treatment
4.1. Experimental Research
4.1.1. CCL2/CCR2 Signaling Pathway and Cerebral Ischemia-Reperfusion Injury
4.1.2. The Potential Application of the CCL2/CCR2 Signaling Pathway in the Treatment of Cerebral Ischemia-Reperfusion
4.2. Clinical Studies
4.2.1. CCL2/CCR2 Signaling Pathway and Cerebral Ischemia-Reperfusion Injury
4.2.2. The Potential Application of the CCL2/CCR2 Signaling Pathway in the Treatment of Cerebral Ischemia-Reperfusion
5. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Number | Species | Animal Model | Gene Type of Animal | Measured Time | Pathological Effects | References |
---|---|---|---|---|---|---|
1 | SD rats | Middle cerebral artery occlusion (MCAO), 90 min | Wildtype (WT) | 24 or 72 h after MCAO | The expression levels of CCL2 and CCR2 were significantly increased, along with microglial activation. | [33] |
2 | Rats | MCAO, 160 min | Wildtype (WT) | 1 h, 6 h, 12 h, and 5 days after MCAO | The CCL2 mRNA expression was significantly increased and remained for 5 days. | [34,35] |
3 | Mice | MCAO, 120 min | CCL2 transgenic mice | 24 to 48 h after MCAO | The infarction volumes were significantly larger in transgenic mice than in wildtype controls, as well as perivascular accumulation of macrophages and neutrophils. | [36] |
4 | Mice | pMCAO | CCL2-deficient mice | 24 h, 36 h, and 2 weeks after MCAO | The infarction volumes, microglia activation, and the accumulation of macrophages were reduced. | [37] |
5 | Mice | MCAO, 30 min | CCR2+/+ and CCR2−/− mice | 1 and 5 days after MCAO | CCR2−/− mice had reduced infarct sizes, BBB permeability, and brain edema, compared with CCR2+/+ mice. | [38] |
6 | Wistar rats | MCAO, 90 min | Wildtype (WT) | 1, 2, 3, 4, 5, and 7 days after MCAO | The macrophages migrated into the brain parenchyma were dependent on the CCL2/CCR2 signaling pathway. | [39,40] |
7 | Mice | MCAO, 60 min | CCL2/CCR2 double-deficient mice | 1, 2, 4, and 7 days after MCAO | The invasion of macrophages and neutrophils was reduced. | [41] |
8 | Mice | MCAO, 45 min | Wildtype (WT) and CCL2-deficient mice | 12 or 36 h after MCAO | BBB leakage and cerebral infarction were reduced in CCL2-deficient mice. | [42,43] |
9 | Mice | Hypoxic-ischemic (HI), 40 min | Wildtype (WT) and CCR2 knockout mice | 5 weeks and 12 weeks after hypoxia-ischemia | The activation of macrophages and microglia was reduced, along with enhanced long-term spatial learning ability of female mice. | [44] |
10 | Mice | MCAO | Wildtype (WT) | 72 h or 2 weeks after MCAO | CCR2 antagonist inhibited the expression of inflammatory cytokines, reduced brain edema and infarction volume, and promoted the recovery of neurological function. | [45,46] |
11 | Rat | Transient global ischemia | Wildtype (WT) | 8 h and 1, 2, 4, and 7 days after reperfusion | CCL2 is related to the delayed neuronal death in the pyramidal neurons. | [47] |
12 | Mice | MCAO, 60 min | Wildtype (WT) | 23 or 47 h after reperfusion | CCL2 levels were markedly increased in plasma, and microglia and leukocytes infiltrated into the brain. | [48] |
13 | Mice | MCAO | Wildtype (WT) | 48 h after MCAO | The mRNA and protein levels of CCL2 were significantly increased, as well as macrophage infiltration and microglial activation | [49] |
14 | Mice | MCAO | Wildtype (WT) | 6–24 h after MCAO | The mRNA and protein levels of CCL2 were significantly increased 24 h after MCAO. | [50] |
15 | Mice | MCAO, 60 min | Wildtype (WT) | 72 h after MCAO | The expression of CCL2 was significantly increased after MCAO. | [51] |
Number | Patients | Types of Research | Sample | Cases | Results | References |
---|---|---|---|---|---|---|
1 | Any stroke | Meta-analysis | Blood | 17,180 | Higher CCL2 levels were associated with the risk of stroke. | [97] |
2 | Ischemic stroke | Analytical study | Serum | 40 | CCL2 levels were increased in ischemic stroke patients. | [98] |
3 | Acute ischemic stroke | Cohort study | Blood | 122 | High CCL2 levels were associated with good collateral status. | [99] |
4 | Hemorrhagic stroke | Comprehensive analysis | Plasma EVs | 31 | High CCL2 levels correlated with detrimental outcomes after stroke. | [100] |
5 | Acute ischemic stroke | Pilot study | Plasma | The levels of plasma CCL2 in patients >60 years was higher, compared with patients ≤60 years old. | [101] | |
6 | Ischemic stroke | Analytical study | Blood | 71 | CCL2 gene polymorphism was associated with stroke. | [102] |
7 | Ischemic stroke | Comparative study | Cerebrospinal fluid | 23 | CCL2-mediated neuroinflammation was involved in the early process of brain injury in ischemic stroke. | [105] |
8 | Ischemic stroke | Analytical study | Blood | 69 | CCL2 level was independently related to clinical outcome scores at specific timepoints with ischemic stroke. | [107] |
9 | Spontaneous intracerebral hemorrhage | Prospective cohort study | Blood | 115 | CCL2 level was associated with poor outcome in patients with intracerebral hemorrhage. | [108] |
10 | Malignant middle cerebral artery infarction | Cytokine antibody array | Serums | 8 | The level of CCL2 may serve as a diagnostic biomarker or drug target for malignant middle cerebral artery infarction. | [109,110] |
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Geng, H.; Chen, L.; Tang, J.; Chen, Y.; Wang, L. The Role of CCL2/CCR2 Axis in Cerebral Ischemia-Reperfusion Injury and Treatment: From Animal Experiments to Clinical Trials. Int. J. Mol. Sci. 2022, 23, 3485. https://doi.org/10.3390/ijms23073485
Geng H, Chen L, Tang J, Chen Y, Wang L. The Role of CCL2/CCR2 Axis in Cerebral Ischemia-Reperfusion Injury and Treatment: From Animal Experiments to Clinical Trials. International Journal of Molecular Sciences. 2022; 23(7):3485. https://doi.org/10.3390/ijms23073485
Chicago/Turabian StyleGeng, Huixia, Luna Chen, Jing Tang, Yi’ang Chen, and Lai Wang. 2022. "The Role of CCL2/CCR2 Axis in Cerebral Ischemia-Reperfusion Injury and Treatment: From Animal Experiments to Clinical Trials" International Journal of Molecular Sciences 23, no. 7: 3485. https://doi.org/10.3390/ijms23073485