Table 2.
Summary of animal studies investigating the role of chemokines in intracerebral hemorrhage.
| Chemokine | Receptor | Species | ICH Model | Methods of inhibition/activation | Time | Effect of chemokines/receptors | References |
|---|---|---|---|---|---|---|---|
| CCL2 | CCR2 | C57BL/6 mice | Collagenase | Genetic deletion | 1 day, 3 days, 7 days, 14 days | CCL2/CCR2 deficiency might decrease hematoma size at early time points but delay the recovery. | Yao and Tsirka (2012a) |
| CCL2 | CCR2 | SD rat | Collagenase | Pharmacological intervention (CCR2 inhibitor propagermanium, oral gavage, three times a day, 25 mg/kg/day for 1 day or 3 days) | 1 day, 3 days | Propagermanium maintain BBB integrity, reduce brain edema, and improve neurobehavioral functions. | Guo et al. (2020) |
| CCL2 | CCR2 | SD rat | Collagenase | Pharmacological intervention (S1PR3 antagonist CAY10444, I.P., 0.5 mg/kg/day for 1 day or 3 days) | 1 day, 3 days | S1PR3 inhibition exerts a neuroprotective effect via the S1P-CCL2-p-p38 MAPK pathway. | Xu et al. (2021) |
| CCL2 | CCR2 | C57BL/6 mice | Collagenase | Genetic deletion; Pharmacological intervention (CCR2 antibody MC-21, I.P., 20 μg before ICH and again 24 h later) | 1 day, 3 days, 7 days | CCR2 deletion and MC-21 decreased inflammatory monocyte recruitment and are protected from early motor deficits | Hammond et al. (2014) |
| CCL2 | / | mouse | Autologous blood | Gene silencing by shRNA | 48 h | MCP-1 shRNA inhibited inflammation response and improved neurological injury | Yang et al. (2016) |
| CCL5 | CCR5 | CD1 mice | Autologous blood | Pharmacological intervention (CCR5 antagonist Maraviroc, intranasally, 50 μg/kg or 150 μg/kg or 450 μg/kg per day for 3 days) | 3 h, 6 h, 12 h, 24 h, 72 h | MVC improved neurobehavioral deficits and decreased neuronal pyroptosis in ipsilateral brain tissues, partially through the CCR5/PKA/CREB/NLRP1 signaling pathway | Yan et al. (2021) |
| CCL5 | CCR1 | CD1 mice | Autologous blood | Pharmacological intervention (CCR1 inhibitor Met-RANTES, intranasally, 0.15 μg/kg or 0.5 μg/kg or 1.5 μg/kg at 1 h post-ICH) | 3 h, 6 h, 12 h, 24 h, 72 h | CCR1 inhibition with Met-RANTES attenuated neuroinflammation, thereby reducing brain edema and improving neurobehavioral functions | Yan et al. (2020) |
| CCL5 | CCR1 | CD1 mice | Autologous blood | Pharmacological intervention (CCR1 antagonist Met-RANTES, intranasally, 0.15 μg/kg or 0.5 μg/kg or 1.5 μg/kg at 1 h post-ICH) | 1 h, 24 h, 72 h, 7 days, 14 days, 21 days, 25 days | Met-R treatment attenuated blood–brain barrier permeability and ameliorated neurobehavioral deficits through inhibiting CCR1/SRC/Rac1 signaling pathway in mice. | Yan et al. (2022) |
| CCL12 | / | C57BL/6 mice | Autologous blood | Genetic deletion. Pharmacological intervention (CCL12 antibody, I.P.) | 1 day, 3 days, 5 days, 7 days | CCL12 deletion attenuated ICH damage in the brain | Huang et al. (2020) |
| CCL17 | CCR4 | CD1 mice | Autologous blood | Pharmacological intervention (CCR4 activator rCCL17, intranasally, 10 μg/kg, 30 μg/kg, 90 μg/kg, at 1 h following ICH) | 6 h, 12 h, 24 h, 72 h, 5 days, 7 days, 14 days, 21 days, 22–27 days | CCR4 activation with rCCL17 promoted hematoma resolution by increasing CD163 expression and CCR4/ERK/Nrf2 pathway, thereby reducing brain edema and improving neurological function | Deng et al. (2020) |
| CCL17 | CCR4 | CD1 mice | Autologous blood | Pharmacological intervention (CCR4 activator, rCCL17, 10 μg/kg, 30 μg/kg, 90 μg/kg, intranasally at 1 h following ICH) | 6 h, 12 h, 24 h, 72 h, 5 days, 7 days, 14 days, 21 days, 22–27 days | rCCL17-dependent CCR4 activation ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the PI3K/AKT/Foxo1 signaling pathway after ICH | Deng et al. (2021) |
| CXCL2 | CXCR1/2 | C57BL/6J mice | Collagenase | Pharmacological intervention (CXCR1/2 antagonist, reparixin) | 0, 3 h, 6 h, 12 h, 24 h | CXCR1/2 antagonist reparixin ameliorated neurological deficits | Matsushita et al. (2014) |
| / | CXCR4 | SD rats, C57BL/6 mice | Collagenase | Pharmacological intervention (CXCR4 agonist CX807, I.P., 3 mg/kg/day for 3 days) | 30 min, 60 min, 90 min, 3 days, 4 days | CX807 is neuroprotective and anti-inflammatory against ICH | Yu et al. (2020) |
| CXCL12 | CXCR4 | SD rats | Collagenase | Pharmacological intervention (CXCL12, I.V., 10 μL every other day; CXCR4 agonist, AMD3100, S.C., 120 μg/kg, twice daily) | 24 h, 14 days | CXCL12 stimulates EPCs to induce angiogenesis though the CXCR4 pathway after ICH | Li et al. (2015) |
| CX3CL1 | CX3CR1 | C57BL/6 mice | Collagenase | Pharmacological intervention (CX3CL1 and a CX3CR1 inhibitor AZD8797, lateral ventricular injection) | 6 h, 12 h, 24 h, 3 days, 7 days | CX3CL1 significantly decreased the hematoma size and Hb content and improved neurological deficits | You et al. (2022) |
| CX3CL1 | CX3CR1 | C57BL/6 mice | Collagenase | Genetic overexpression | 6 h, 12 h, 1 day, 2 days, 3 days, 5 days, 7 days | The overexpression of CX3CR1 increased the migration ability of adipose derived stem cells, reduced cell death and improved sensory and motor functions | Li G. et al. (2019) |
BBB, blood–brain barrier; I.P., intraperitoneal injection; I.V., intravenous injection; S.C., subcutaneous injection; EPCs, endothelial progenitor cells.