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Fluids and Barriers of the CNS
Published in: Fluids and Barriers of the CNS 1/2023

Open Access 01-12-2023 | Cerebral Edema | Research

Inhibition of lysophosphatidic acid receptor 1 relieves PMN recruitment in CNS via LPA1/TSP1/CXCR2 pathway and alleviates disruption on blood-brain barrier following intracerebral haemorrhage in mice

Authors: Ling Gao, Li Peng, Prativa Sherchan, Hong Tang, Yu Liu, Jie Xiao, Hui Shi, Yujie Luo, Jiping Tang, John H. Zhang, Ying Xia

Published in: Fluids and Barriers of the CNS | Issue 1/2023

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Abstract

Backgroud

The frequencies of morbidity and impairment associated with spontaneous intracerebral haemorrhage (ICH) are comparatively high. Blood-brain barrier (BBB) integrity was compromised due to subsequent brain injury induced by ICH, which is crucial for a poor prognosis. Polymorphonuclear leukocyte (PMN) strongly modulate the disruption of BBB in the central nervous system (CNS). The lysophosphatidic acid receptor 1 (LPA1) mediated thrombospondin-1 (TSP1) regulation in astrocytes, which induce macrophage inflammatory protein 2(MIP2) secretion. MIP2 enhance PMN recruitment through CXC chemokine type 2 (CXCR2) activation. The purpose of this study was to investigate whether the LPA1-mediated inhibition of PMN recruitment and BBB protection after ICH is regulated by TSP1 and CXCR2 networks.

Methods

ICH induction was performed in CD1 mice using collagenase administration. AM966, a targeted LPA1 antagonist, was orally administered 1 and 12 h following ICH. further identify possible LPA1-mediated BBB protection mechanisms, we intracerebroventricularly (ICV) administered a CXCR2 ligand MIP2, as well as TSP1 CRISPR activation (ACT) with AM966. Consequently, we performed neurobehavioral, brain water content (BWC), Evans blue staining (EBS), immunofluorescence (IF), and western blot (WB) analyses.

Results

After ICH, astrocytes showed signs of LPA1, which peaked after 24 h, while PMN\ displayed evidence of CXCR2. The AM966-mediated LPA1 suppression relieved PMN recruitment, diminished brain oedema, demonstrated extravasation (as evidenced by EBS), protected BBB integrity, and enhanced neurologic activity following ICH. AM966 treatment strongly reduced TSP1, CXCR2, Occludin, and Claudin-5 expressions and PMN recruitment following ICH, and their expressions were restored by MIP2 and TSP1 CRISPR (ACT).

Conclusions

This study shows that LAP1 suppression reduced PMN recruitment after ICH in mice via TSP1/CXCR2 signalling, which minimized BBB disruption and improved the CNS’s neurobehavioral functioning. Hence, LPA1 is a strong candidate for therapy to reduce PMN recruitment and offer protection of BBB integrity after ICH.
Appendix
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Metadata
Title
Inhibition of lysophosphatidic acid receptor 1 relieves PMN recruitment in CNS via LPA1/TSP1/CXCR2 pathway and alleviates disruption on blood-brain barrier following intracerebral haemorrhage in mice
Authors
Ling Gao
Li Peng
Prativa Sherchan
Hong Tang
Yu Liu
Jie Xiao
Hui Shi
Yujie Luo
Jiping Tang
John H. Zhang
Ying Xia
Publication date
01-12-2023
Publisher
BioMed Central
Keyword
Cerebral Edema
Published in
Fluids and Barriers of the CNS / Issue 1/2023
Electronic ISSN: 2045-8118
DOI
https://doi.org/10.1186/s12987-023-00434-3

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