Back to Search
Start Over
Sphingosine-1-phosphate receptor 3 is implicated in BBB injury via the CCL2-CCR2 axis following acute intracerebral hemorrhage.
- Source :
-
CNS neuroscience & therapeutics [CNS Neurosci Ther] 2021 Jun; Vol. 27 (6), pp. 674-686. Date of Electronic Publication: 2021 Feb 28. - Publication Year :
- 2021
-
Abstract
- 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.<br />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.<br />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.<br />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.<br /> (© 2021 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)
- Subjects :
- Animals
Brain Edema diagnostic imaging
Cell Proliferation
Cerebral Hemorrhage drug therapy
Cerebral Hemorrhage psychology
Humans
Macrophage Activation
Magnetic Resonance Imaging
Male
Microglia
Psychomotor Performance
RNA-Seq
Rats
Rats, Sprague-Dawley
Sphingosine-1-Phosphate Receptors antagonists & inhibitors
Thiazolidines therapeutic use
Tomography, X-Ray Computed
Blood-Brain Barrier injuries
Cerebral Hemorrhage genetics
Chemokine CCL4 genetics
Receptors, CCR2 genetics
Sphingosine-1-Phosphate Receptors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1755-5949
- Volume :
- 27
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- CNS neuroscience & therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 33645008
- Full Text :
- https://doi.org/10.1111/cns.13626