Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage

Guo, Fuyou; Xu, Dingkang; Lin, Yu Cheng; Wang, Guoqing; Wang, Fang; Gao, Qiang; Wei, Qi; Lei, Shixiong

doi:10.1096/fj.201902203rr

Cited by 61 publications

(54 citation statements)

References 36 publications

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“…However, CCL-2 was significantly less induced in the TLR4 mut mice compared with the TLR4 WT mice at days 4 and 6 PI, but was induced to similar levels at day 8 PI (Figure 3d). CCL-2 attracts monocytes and T cells as well as contributes to BBB permeability [33]. The reduced inductions of MMP-9, MMP-2, CCL-2 and ICAM-1 in the TLR4 mut mice support the role of TLR4 mediating BBB permeability during VEEV infection.…”

Section: Impaired Tlr4 Signaling Reduces the Upregulation Of Bbb Permeability-related Proteins During Veev Tc-83 Infectionmentioning

confidence: 61%

Toll-like receptor 4 mediates blood-brain barrier permeability and disease in C3H mice during Venezuelan equine encephalitis virus infection

et al. 2021

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Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus that can cause debilitating, acute febrile illness and potentially result in encephalitis. Currently, there are no FDA-licensed vaccines or specific therapeutics for VEEV. Previous studies have demonstrated that VEEV infection results in increased blood-brain barrier (BBB) permeability that is mediated by matrix metalloproteinases (MMPs). Furthermore, after subarachnoid hemorrhage in mice, MMP-9 is upregulated in the brain and mediates BBB permeability in a toll-like receptor 4 (TLR4)-dependent manner. Here, we demonstrate that disease in C3H mice during VEEV TC-83 infection is dependent on TLR4 because intranasal infection of C3H/HeN (TLR4 WT ) mice with VEEV TC-83 resulted in mortality as opposed to survival of TLR4-defective C3H/HeJ (TLR4 mut ) mice. In addition, BBB permeability was induced to a lesser extent in TLR4 mut mice compared with TLR4 WT mice during VEEV TC-83 infection as determined by sodium fluorescein and fluorescently-conjugated dextran extravasation. Moreover, MMP-9, MMP-2, ICAM-1, CCL2 and IFN-γ were all induced to significantly lower levels in the brains of infected TLR4 mut mice compared with infected TLR4 WT mice despite the absence of significantly different viral titers or immune cell populations in the brains of infected TLR4 WT and TLR4 mut mice. These data demonstrate the critical role of TLR4 in mediating BBB permeability and disease in C3H mice during VEEV TC-83 infection, which suggests that TLR4 is a potential target for the development of therapeutics for VEEV.

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Section: Impaired Tlr4 Signaling Reduces the Upregulation Of Bbb Permeability-related Proteins During Veev Tc-83 Infectionmentioning

confidence: 61%

Toll-like receptor 4 mediates blood-brain barrier permeability and disease in C3H mice during Venezuelan equine encephalitis virus infection

et al. 2021

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“…The human cerebral microvascular endothelial cell line hCMEC/D3 and a human astrocyte (HA) cell line were generous gifts from the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences. A coculture model was developed in our previous study 11 . Three to four days after the initial coculture, S1P (1 µM, Apexbio, USA) and CAY10444 (1 µM, Glpbio, USA) were added to the endothelial side.…”

Section: Methodsmentioning

confidence: 99%

Sphingosine‐1‐phosphate receptor 3 is implicated in BBB injury via the CCL2‐CCR2 axis following acute intracerebral hemorrhage

Gao

Wang

et al. 2021

CNS Neurosci Ther

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Background Intracerebral 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. Methods We 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. Results The 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. Conclusion To 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.

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“…Previous studies found that, MAPK pathway can active FoxO family [25]. Interestingly, autocrine CCL2 is associated with activation MAPK pathway [26]. We next investigated the relationship between MAPK pathway and FoxO1 activity in response to rCCL2 stimulation in macrophage.…”

Section: Ccl2 Induces Foxo1 Activation Via P38 Mapk Pathway In Thp-1 mentioning

confidence: 95%

CircRNA hsa_circ_0110102 Function as Anti-Oncogenic Gene in Hepatocellular Carcinoma Through Modulating miR-580-5p/CCL2 Pathway

Wang

Wei

et al. 2020

Preprint

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Background: Circular RNAs (circRNAs) have been shown to have critical regulatory roles in tumor biology, whereas their contributions in hepatocellular carcinoma (HCC) still remains enigmatic. The purpose of this study was to investigate the molecular mechanisms involved in hsa_circ_0110102 in the occurrence and development of HCC. Methods: The expression levels of hsa_circ_0110102 in HCC cell lines and tissues were estimated by RT-qPCR assay. The proliferation, migration, and invasion of HCC cells were determined by CCK-8 and transwell assay. The western blot and ELISA were employed to examine the related-protein and cytokine expression. The association between miR-580-5p and hsa_circ_0110102 or CCL2 was predicted and affirmed by dual-luciferase reporter assay and RNA pull-down.Results: hsa_circ_0110102 was significantly down-regulated in HCC cell lines and tissues, low hsa_circ_0110102 expression levels were associated with poor prognosis. Knockdown hsa_circ_0110102 significantly inhibited cell proliferation, migration and invasion. In addition, luciferase assay and RNA pull-down assay indicating that hsa_circ_0110102 function as sponge for miR-580-5p. Moreover, miR-580-5p which could directly bind to the 3’-UTR of CCL2 and induce its expression, then active the COX-2/PGE2 pathway in macrophage via FoxO1 in p38 MAPK dependent manner. Furthermore, the Δ256 mutant of FoxO1 showed no activation effect. Conclusion: hsa_circ_0110102 act as a sponge for miR-580-5p and decreased CCL2 secretion in HCC cells, then inhibits pro-inflammatory cytokine release from activated macrophage by regulating the COX-2/PGE2 pathway. These results indicating that hsa_circ_0110102 serves as a potential prognostic predictor or therapeutic target for HCC.

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Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage

Cited by 61 publications

References 36 publications

Toll-like receptor 4 mediates blood-brain barrier permeability and disease in C3H mice during Venezuelan equine encephalitis virus infection

Toll-like receptor 4 mediates blood-brain barrier permeability and disease in C3H mice during Venezuelan equine encephalitis virus infection

Sphingosine‐1‐phosphate receptor 3 is implicated in BBB injury via the CCL2‐CCR2 axis following acute intracerebral hemorrhage

CircRNA hsa_circ_0110102 Function as Anti-Oncogenic Gene in Hepatocellular Carcinoma Through Modulating miR-580-5p/CCL2 Pathway

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