小鼠预处理的神经保护依赖于MyD88介导的CXCL10在内皮细胞中的表达。

IF 3.9 4区 医学 Q2 NEUROSCIENCES ASN NEURO Pub Date : 2023-01-01 DOI:10.1177/17590914221146365
Zhihong Chen, Weiwei Hu, Mynor J Mendez, Zachary C Gossman, Anthony Chomyk, Brendan T Boylan, Grahame J Kidd, Timothy W Phares, Cornelia C Bergmann, Bruce D Trapp
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引用次数: 0

摘要

中枢神经系统(CNS)可以通过低剂量革兰氏阴性细菌内毒素脂多糖(LPS)的外周预处理来预处理以抵抗损伤。与大脑皮层对创伤性脑损伤的瞬时保护相关的潜在机制包括抗凋亡和神经营养分子的神经元产生增加,小胶质细胞介导的支配皮层投射神经元胞体的抑制性突触前终末的移位,以及皮层投射神经元的同步放电。然而,负责这些神经元和小胶质细胞变化的细胞类型和信号传导尚不清楚。一个根本问题是LPS是否穿透中枢神经系统或作用于脑内皮细胞的管腔表面,从而触发间接的实质神经保护反应。本研究表明,低剂量腹膜内LPS治疗增加了脑内皮细胞活化标志物CD54,但不会打开血脑屏障或改变脑内皮细胞紧密连接,如电子显微镜所评估的。CD31阳性脑内皮细胞的NanoString nCounter转录物分析进一步揭示了Cxcl10、C3、Ccl2、Il1β、Cxcl2和Cxcl1的显著上调,这与通过通路分析鉴定髓系分化初级反应88(MyD88)是这些转录物的调节剂相一致。条件遗传内皮细胞基因消融方法表明,MyD88依赖性Toll样受体4(TLR4)信号传导和Cxcl10表达对LPS诱导的神经保护和小胶质细胞活化至关重要。这些结果表明,内皮细胞响应循环TLR配体产生的C-X-C基序趋化因子配体10(CXCL10)可能直接或间接向神经元和/或小胶质细胞上的CXCR3发出信号。因此,脑内皮受体的靶向激活可以为诱导短暂的神经保护提供一种有吸引力的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Neuroprotection by Preconditioning in Mice is Dependent on MyD88-Mediated CXCL10 Expression in Endothelial Cells.

The central nervous system (CNS) can be preconditioned to resist damage by peripheral pretreatment with low-dose gram-negative bacterial endotoxin lipopolysaccharide (LPS). Underlying mechanisms associated with transient protection of the cerebral cortex against traumatic brain injury include increased neuronal production of antiapoptotic and neurotrophic molecules, microglial-mediated displacement of inhibitory presynaptic terminals innervating the soma of cortical projection neurons, and synchronized firing of cortical projection neurons. However, the cell types and signaling responsible for these neuronal and microglial changes are unknown. A fundamental question is whether LPS penetrates the CNS or acts on the luminal surface of brain endothelial cells, thereby triggering an indirect parenchymal neuroprotective response. The present study shows that a low-dose intraperitoneal LPS treatment increases brain endothelial cell activation markers CD54, but does not open the blood-brain barrier or alter brain endothelial cell tight junctions as assessed by electron microscopy. NanoString nCounter transcript analyses of CD31-positive brain endothelial cells further revealed significant upregulation of Cxcl10, C3, Ccl2, Il1β, Cxcl2, and Cxcl1, consistent with identification of myeloid differentiation primary response 88 (MyD88) as a regulator of these transcripts by pathway analysis. Conditional genetic endothelial cell gene ablation approaches demonstrated that both MyD88-dependent Toll-like receptor 4 (TLR4) signaling and Cxcl10 expression are essential for LPS-induced neuroprotection and microglial activation. These results suggest that C-X-C motif chemokine ligand 10 (CXCL10) production by endothelial cells in response to circulating TLR ligands may directly or indirectly signal to CXCR3 on neurons and/or microglia. Targeted activation of brain endothelial receptors may thus provide an attractive approach for inducing transient neuroprotection.

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来源期刊
ASN NEURO
ASN NEURO NEUROSCIENCES-
CiteScore
7.70
自引率
4.30%
发文量
35
审稿时长
>12 weeks
期刊介绍: ASN NEURO is an open access, peer-reviewed journal uniquely positioned to provide investigators with the most recent advances across the breadth of the cellular and molecular neurosciences. The official journal of the American Society for Neurochemistry, ASN NEURO is dedicated to the promotion, support, and facilitation of communication among cellular and molecular neuroscientists of all specializations.
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