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The CCL2-CCR2 system affects the progression and clearance of intracerebral hemorrhage.

ABSTRACT: Intracerebral hemorrhage (ICH) has been associated with inflammation and apoptosis. The CCL2-CCR2 chemotactic system is one of the major signaling pathways that induce inflammation and apoptosis. However, its role on ICH has not been investigated. We subjected wild-type, CCL2(-/-) , and CCR2(-/-) mice to collagenase-induced ICH, and assessed histological and behavioral outcomes. Lack of CCL2 or CCR2 decreased the hematoma volume early after collagenase-induced ICH but delayed its recovery. The hematoma size was accompanied by brain edema, neuronal death, and neurological scores. Although microglia activation/migration was attenuated in CCL2(-/-) or CCR2(-/-) mice 1 day after injury, more microglia were present at later time points, suggesting that alternative signaling pathways had been activated to recruit them. On the contrary, leukocyte and neutrophil infiltration were decreased in these mice, suggesting a tighter/recovered blood-brain barrier. In addition, we also found that FL- and K104Stop-CCL2 were able to restore the changes found in CCL2(-/-) mice, but K104A-CCL2 failed to do so. These results suggest that plasmin-mediated truncation of CCL2 may be an indispensable step to fully activate the chemokine in vivo. The data also indicate that CCL2-CCR2 signaling pathway may be a molecular target for the treatment of ICH.

SUBMITTER: Yao Y

PROVIDER: S-EPMC3325358 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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The CCL2-CCR2 system affects the progression and clearance of intracerebral hemorrhage.

Yao Yao Y Tsirka Stella E SE

Glia 20120314 6

Intracerebral hemorrhage (ICH) has been associated with inflammation and apoptosis. The CCL2-CCR2 chemotactic system is one of the major signaling pathways that induce inflammation and apoptosis. However, its role on ICH has not been investigated. We subjected wild-type, CCL2(-/-) , and CCR2(-/-) mice to collagenase-induced ICH, and assessed histological and behavioral outcomes. Lack of CCL2 or CCR2 decreased the hematoma volume early after collagenase-induced ICH but delayed its recovery. The h ...[more]

PMID: 22419223

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Project description:BackgroundIntracerebral hemorrhage (ICH) is a catastrophic cerebrovascular disease with high morbidity and mortality. Evidence demonstrated that sphingosine-1-phosphate receptor (S1PR) plays a vital role in inflammatory damage via the upregulation of CCL2 expression. However, whether S1PR3 is involved in blood-brain barrier (BBB) breakdown via CCL2 activation after ICH has not been described.MethodsWe investigated the expression profiles of all S1PRs using high-throughput RNA-seq analysis and RT-PCR. The potential role of S1PR3 and interaction between S1PR3 and CCL2 were evaluated via Western blotting, immunofluorescence, and flow cytometry. BBB disruption was examined via magnetic resonance imaging, transmission electron microscopy, and Evans blue extravasation. Microglial activation, proliferation, and polarization were assessed via histopathological analysis. The expression levels of CCL2, p-p38 MAPK, ICAM-1, and ZO-1 were examined in vitro and in vivo.ResultsThe present results showed that the levels of S1PR3 and its ligand, sphingosine 1-phosphate (S1P), were dramatically increased following ICH, which regulated the expression of CCL2 and p38MAPK. Moreover, reductions in brain edema volume, amelioration of BBB integrity, and improvements in behavioral deficits were achieved after the administration of CAY10444, an S1PR3 antagonist, to rats. Remarkably increased CCL2, p-p38MAPK, and ICAM-1 expression and decreased ZO-1 expression were observed in cocultured human astrocytes (HAs) and hCMEC/D3 cells after S1P stimulation. However, the expression levels of CCL2, p-p38 MAPK, and ICAM-1 were decreased and ZO-1 expression was increased after S1PR3 inhibition. In addition, microglial proliferation and M1 polarization were attenuated after CAY10444 administration.ConclusionTo the best of our knowledge, this is the first demonstration of the neuroprotective role of S1PR3 modulation in maintaining BBB integrity by inhibiting the S1PR3-CCL2 axis after ICH, providing a novel treatment for ICH by targeting S1PR3.

Project description:Background: Age-related macular degeneration (AMD) is the most common cause of progressive and irreversible blindness in developed countries. Although the pathogenesis is not fully understood, AMD is a multifactorial pathology with an accumulation of inflammatory components and macrophages and a strong genetic predisposition. Our purpose was to investigate the association between early AMD and CCL2 (rs1024611, rs4586, rs2857656) and CCR2 (rs1799865) single nucleotide polymorphisms (SNPs) and CCL2, CCR2 serum levels in a Lithuanian population. Methods: The study included 310 patients with early AMD and 384 healthy subjects. Genotyping of CCL2 rs1024611, rs4586, rs2857656, and CCR2 rs1799865 was performed using a real-time polymerase chain reaction method, while CCL2 and CCR2 chemokines serum concentrations were analyzed using an enzyme-linked immunosorbent assay. Results: We found that the G allele at CCL2 rs1024611 was more prevalent in the early AMD group than in controls (29.2% vs. 24.1%, p = 0.032). Similarly, the C allele in CCL2 rs2857656 is more common in the early AMD group than in controls (29.2% vs. 24.2%, p = 0.037). Binomial logistic regression revealed that each G allele in rs1024611 was associated with 1.3-fold increased odds of developing early AMD under the additive model (OR = 1.322; 95% CI: 1.032–1.697, p = 0.027) as was each C allele in rs2857656 under the additive model (OR = 1.314; 95% CI: 1.025–1.684, p = 0.031). Haplotype analysis revealed that the C-A-G haplotype of CCL2 SNPs was associated with 35% decreased odds of early AMD development. Further analysis showed elevated CCL2 serum levels in the group with early AMD compared to controls (median (IQR): 1181.6 (522.6) pg/mL vs. 879.9 (494.4) pg/mL, p = 0.013); however, there were no differences between CCR2 serum levels within groups. Conclusions: We found the associations between minor alleles at CCL2 rs1024611 and rs2857656, elevated CCL2 serum levels, and early AMD development.

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The CCL2-CCR2 system affects the progression and clearance of intracerebral hemorrhage.

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The CCL2-CCR2 system affects the progression and clearance of intracerebral hemorrhage.

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