PDF(Pubmed)
Abstract：
Leukocyte common antigen-related phosphatase (LAR) is widely expressed in the central nervous system and is known to regulate a variety of processes including cell growth, differentiation, and inflammation. However, little is currently known about LAR signaling mediated neuroinflammation after intracerebral hemorrhage (ICH). The objective of this study was to investigate the role of LAR in ICH using autologous blood injection-induced ICH mouse model. Expression of endogenous proteins, brain edema and neurological function after ICH were evaluated. Extracellular LAR peptide (ELP), an inhibitor of LAR, was administered to ICH mice and outcomes were evaluated. LAR activating-CRISPR or IRS inhibitor NT-157 was administered to elucidate the mechanism. The results showed that expressions of LAR, its endogenous agonist chondroitin sulfate proteoglycans (CSPGs) including neurocan and brevican, and downstream factor RhoA increased after ICH. Administration of ELP reduced brain edema, improved neurological function, and decreased microglia activation after ICH. ELP decreased RhoA and phosphorylated serine-IRS1, increased phosphorylated tyrosine-IRS1 and p-Akt, and attenuated neuroinflammation after ICH, which was reversed by LAR activating-CRISPR or NT-157. In conclusion, this study demonstrated that LAR contributed to neuroinflammation after ICH via RhoA/IRS-1 pathway, and ELP may be a potential therapeutic strategy to attenuate LAR mediated neuroinflammation after ICH.
摘要：
白细胞共同抗原相关磷酸酶（LAR）在中枢神经系统中广泛表达，并且已知可调节多种过程，包括细胞生长，分化,和炎症。然而,目前对脑出血(ICH)后LAR信号介导的神经炎症知之甚少.本研究的目的是使用自体血液注射诱导的ICH小鼠模型研究LAR在ICH中的作用。内源性蛋白质的表达，评估脑出血后的脑水肿和神经功能。细胞外LAR肽（ELP），LAR的抑制剂,对ICH小鼠进行给药并评估结果。施用LAR激活-CRISPR或IRS抑制剂NT-157以阐明机制。结果表明,LAR的表达,其内源性激动剂硫酸软骨素蛋白聚糖（CSPGs），包括neurocan和brevican，ICH后下游因子RhoA增加。给予ELP减少脑水肿，改善神经功能，ICH后小胶质细胞活化减少。ELP降低RhoA和磷酸化丝氨酸-IRS1，增加磷酸化酪氨酸-IRS1和p-Akt，减轻ICH后的神经炎症，它被LAR激活-CRISPR或NT-157逆转。总之,这项研究表明，LAR通过RhoA/IRS-1途径促进ICH后的神经炎症，和ELP可能是减轻ICH后LAR介导的神经炎症的潜在治疗策略。
