Recombinant Slit2 attenuates neuroinflammation after surgical brain injury by inhibiting peripheral immune cell infiltration via Robo1-srGAP1 pathway in a rat model

NEUROBIOLOGY OF DISEASE

卷:85

Article

Sherchan, Prativa¹  Huang, Lei^1,2  Wang, Yuechun¹  Akyol, Onat¹  Tang, Jiping¹  Zhang, John H.^1,2,3 

[1] Loma Linda Univ, Dept Physiol & Pharmacol, Loma Linda, CA 92354 USA

[2] Loma Linda Univ, Dept Anesthesiol, Loma Linda, CA 92354 USA

[3] Loma Linda Univ, Dept Neurosurg, Loma Linda, CA 92354 USA

关键词: Surgical brain injury;    Neuroinflammation;    Brain edema;    Peripheral immune cell infiltration;    Slit2;    Robo1;    srGAP1;    Cdc42;   

DOI  :  10.1016/j.nbd.2015.11.003

来源: Elsevier

【 摘 要 】

Background and purpose: Peripheral immune cell infiltration to the brain tissue at the perisurgical site can promote neuroinflammation after surgical brain injury (SBI). Slit2, an extracellular matrix protein, has been reported to reduce leukocyte migration. This study evaluated the effect of recombinant Slit2 and the role of its receptor roundabout1 (Robo1) and its downstream mediator Slit-Robo GTPase activating protein I (srGAP1)-Cdc42 on peripheral immune cell infiltration after SBI in a rat model. Methods: One hundred and fifty-three adult male Sprague-Dawley rats (280-350 g) were used. Partial resection of right frontal lobe was performed to induce SBI. Slit2 siRNA was administered by intracerebroventricular injection 24 h before SBI. Recombinant Slit2 was injected intraperitoneally 1 h before SBI. Recombinant Robol used as a decoy receptor was co-administered with recombinant Slit2. srGAP1 siRNA was administered by intracerebroventricular injection 24 h before SBI. Post-assessments included brain water content measurement, neurological tests, ELISA, Western blot, immunohistochemistry, and Cdc42 activity assay. Results: Endogenous Slit2 was increased after SBI. Robol was expressed by peripheral immune cells. Endogenous Slit2 knockdown worsened brain edema after SBI. Recombinant Slit2 administration reduced brain edema, neurological deficits, and pro-inflammatory cytokines after SBI. Recombinant Slit2 reduced peripheral immune cell markers cluster of differentiation 45 (CD45) and myeloperoxidase (MPO), as well as Cdc42 activity in the perisurgical brain tissue which was reversed by recombinant Robol co-administration and srGAP1 siRNA. Conclusions: Recombinant Slit2 improved outcomes by reducing neuroinflammation after SBI, possibly by decreasing peripheral immune cell infiltration to the perisurgical site through Robo1-srGAP1 mediated inhibition of Cdc42 activity. These results suggest that Slit2 may be beneficial to reduce SBI-induced neuroinflammation. (C) 2015 Elsevier Inc. All rights reserved.

【 授权许可】

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