Recombinant Slit2 suppresses neuroinflammation and Cdc42-mediated brain infiltration of peripheral immune cells via Robo1-srGAP1 pathway in a rat model of germinal matrix hemorrhage

作者全名："Li, Qian; Huang, Lei; Ding, Yan; Sherchan, Prativa; Peng, Wenjie; Zhang, John H."

作者地址："[Li, Qian; Peng, Wenjie] Army Med Univ, Army Med Ctr, Dept Pediat, 10 Changjiang Access Rd, Chongqing 400042, Peoples R China; [Li, Qian] Chongqing Med Univ, Women & Childrens Hosp, 120 Longshan Access Rd, Chongqing 400010, Peoples R China; [Huang, Lei; Ding, Yan; Sherchan, Prativa; Zhang, John H.] Loma Linda Univ, Sch Med, Dept Physiol & Pharmacol, 11041 Campus St, Loma Linda, CA 92354 USA; [Huang, Lei; Zhang, John H.] Loma Linda Univ, Sch Med, Dept Neurosurg, 11234 Anderson St, Loma Linda, CA 92354 USA"

通信作者："Zhang, JH (通讯作者)，Loma Linda Univ, Sch Med, Dept Physiol & Pharmacol, 11041 Campus St, Loma Linda, CA 92354 USA.; Zhang, JH (通讯作者)，Loma Linda Univ, Sch Med, Dept Neurosurg, 11234 Anderson St, Loma Linda, CA 92354 USA."

来源：JOURNAL OF NEUROINFLAMMATION

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001094040300001

JCR分区：Q1

影响因子：9.3

年份：2023

卷号：20

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Germinal matrix hemorrhage; Slit2; Robo1-srGAP1; Neuroinflammation; Apoptosis; Rat

摘要："BackgroundGerminal matrix hemorrhage (GMH) is a devastating neonatal stroke, in which neuroinflammation is a critical pathological contributor. Slit2, a secreted extracellular matrix protein, plays a repulsive role in axon guidance and leukocyte chemotaxis via the roundabout1 (Robo1) receptor. This study aimed to explore effects of recombinant Slit2 on neuroinflammation and the underlying mechanism in a rat model of GMH.MethodsGMH was induced by stereotactically infusing 0.3 U of bacterial collagenase into the germinal matrix of 7-day-old Sprague Dawley rats. Recombinant Slit2 or its vehicle was administered intranasally at 1 h after GMH and daily for 3 consecutive days. A decoy receptor recombinant Robo1 was co-administered with recombinant Slit2 after GMH. Slit2 siRNA, srGAP1 siRNA or the scrambled sequences were administered intracerebroventricularly 24 h before GMH. Neurobehavior, brain water content, Western blotting, immunofluorescence staining and Cdc42 activity assays were performed.ResultsThe endogenous brain Slit2 and Robo1 expressions were increased after GMH. Robo1 was expressed on neuron, astrocytes and infiltrated peripheral immune cells in the brain. Endogenous Slit2 knockdown by Slit2 siRNA exacerbated brain edema and neurological deficits following GMH. Recombinant Slit2 (rSlit2) reduced neurological deficits, proinflammatory cytokines, intercellular adhesion molecules, peripheral immune cell markers, neuronal apoptosis and Cdc42 activity in the brain tissue after GMH. The anti-neuroinflammation effects were reversed by recombinant Robo1 co-administration or srGAP1 siRNA.ConclusionsRecombinant Slit2 reduced neuroinflammation and neuron apoptosis after GMH. Its anti-neuroinflammation effects by suppressing onCdc42-mediated brain peripheral immune cells infiltration was at least in part via Robo1-srGAP1 pathway. These results imply that recombinant Slit2 may have potentials as a therapeutic option for neonatal brain injuries."

基金机构：Not applicable.

基金资助正文：Not applicable.