Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β-catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide
Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β-catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide
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DOI：
10.1111/bpa.12798
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发表时间：
2019-11-06
期刊：
影响因子：
6.4
通讯作者：
Deng, Yiyu
中科院分区：
文献类型：
--
作者：
Huang, Peixian;Zhou, Qiuping;Deng, Yiyu
神经炎症被认为在新生儿败血症所致脑室周围白质损伤(PWMD)的发病机制中起关键作用。由于补体级联与炎症反应有关，本研究旨在确定C3a是否参与PWMD，如果是，是否会导致轴突髓鞘减少。此外，我们还探讨了C3a是否通过其C3a受体(C3aR)发挥作用，从而通过Wnt/β-catenin信号通路抑制少突胶质前体细胞(OPC)的成熟。给1日龄SD大鼠腹腔注射脂多糖(1 mg/kg)。注射内毒素后7d，脉宽调制组小胶质细胞和星形胶质细胞中C3a表达上调。同时，NG2(+)少突胶质细胞(OLs)的C3aR表达增强。28天脓毒症大鼠的脉宽调制中，髓鞘蛋白CNPase、PLP、MBP和MAG显著减少。PLP+、MBP+细胞数量明显减少。在电子显微镜下，髓鞘厚度变薄，平均G值较高。伴随着NG2(+)细胞数量的增加和CC1(+)细胞数量的减少。注射脂多糖后，大鼠脉宽调制区的寡核苷酸、寡核苷酸和Sox10蛋白的表达明显减少。C3aRa前7d给药可逆转脓毒症大鼠上述脉宽调制的病理改变。原代培养的OPC与C3a共同孵育后，MBP、CNPase、PLP、MAG、Opol1、Opol2、Sox10和CC1的表达明显下调，而NG2表达增加。此外，WNT/β-catenin信号通路在体外可抑制C3a诱导的OPC的成熟和分化。由此推测，脓毒症大鼠脉宽调制中的C3a可能通过Wnt/β-catenin信号通路与OPC分化成熟障碍密切相关，最终导致轴突髓鞘减少。
Neuroinflammation is thought to play a pivotal role in the pathogenesis of periventricular white matter (PWM) damage (PWMD) induced by neonatal sepsis. Because the complement cascade is implicated in inflammatory response, this study was carried out to determine whether C3a is involved in PWMD, and, if so, whether it would induce axonal hypomyelination. Furthermore, we explored if C3a would act through its C3a receptor (C3aR) and thence inhibit maturation of oligodendrocyte precursor cells (OPCs) via the WNT/beta-catenin signal pathway. Sprague Dawley (SD) rats aged 1 day were intraperitoneally injected with lipopolysaccharide (LPS) (1 mg/kg). C3a was upregulated in activated microglia and astrocytes in the PWM up to 7 days after LPS injection. Concomitantly, enhanced C3aR expression was observed in NG2(+) oligodendrocytes (OLs). Myelin proteins including CNPase, PLP, MBP and MAG were significantly reduced in the PWM of 28-day septic rats. The number of PLP+ and MBP+ cells was markedly decreased. By electron microscopy, myelin sheath thickness was thinner and the average g-ratios were higher. This was coupled with an increase in number of NG2(+) cells and decreased number of CC1(+) cells. Olig1, Olig2 and SOX10 protein expression was significantly reduced in the PWM after LPS injection. Very strikingly, C3aRa administration for the first 7 days could reverse the above-mentioned pathological alterations in the PWM of septic rats. When incubated with C3a, expression of MBP, CNPase, PLP, MAG, Olig1, Olig2, SOX10 and CC1 in primary cultured OPCs was significantly downregulated as opposed to increased NG2. Moreover, WNT/beta-catenin signaling pathway was found to be implicated in inhibition of OPCs maturation and differentiation induced by C3a in vitro. As a corollary, it is speculated that C3a in the PWM of septic rats is closely associated with the disorder of OPCs differentiation and maturation through WNT/beta-catenin signaling pathway, which would contribute ultimately to axonal hypomyelination.