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/β-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/β-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/β-catenin signaling pathway, which would contribute ultimately to axonal hypomyelination.

中文翻译：

---

在脂多糖实验诱导的脓毒症新生大鼠中，补体 C3a 通过激活 WNT/β-catenin 信号通路诱导脑室周围白质的轴突髓鞘形成。

神经炎症被认为在新生儿败血症引起的脑室周围白质 (PWM) 损伤 (PWMD) 的发病机制中起关键作用。由于补体级联反应与炎症反应有关，因此进行这项研究是为了确定 C3a 是否参与 PWMD，如果是，则它是否会诱导轴突髓鞘形成不足。此外，我们探索了 C3a 是否会通过其 C3a 受体 (C3aR) 起作用，从而通过 WNT/β-连环蛋白信号通路抑制少突胶质细胞前体细胞 (OPCs) 的成熟。给 1 天大的 Sprague Dawley (SD) 大鼠腹膜内注射脂多糖 (LPS) (1 mg/kg)。在注射 LPS 后长达 7 天，C3a 在 PWM 中活化的小胶质细胞和星形胶质细胞中上调。同时，在 NG2+ 少突胶质细胞 (OL) 中观察到 C3aR 表达增强。包括 CNPase、PLP、MBP 和 MAG 在内的髓鞘蛋白在 28 天败血症大鼠的 PWM 中显着降低。PLP+和MBP+细胞的数量显着减少。通过电子显微镜，髓鞘厚度更薄，平均 g 比更高。这与 NG2+ 细胞数量的增加和 CC1+ 细胞数量的减少相结合。LPS 注射后 PWM 中 Olig1、Olig2 和 SOX10 蛋白表达显着降低。非常惊人的是，前 7 天的 C3aRa 给药可以逆转上述脓毒症大鼠 PWM 的病理改变。当与 C3a 一起孵育时，原代培养的 OPCs 中 MBP、CNPase、PLP、MAG、Olig1、Olig2、SOX10 和 CC1 的表达显着下调，而不是 NG2 增加。而且，发现 WNT/β-catenin 信号通路参与抑制 C3a 体外诱导的 OPCs 成熟和分化。作为推论，推测脓毒症大鼠 PWM 中的 C3a 与 OPCs 分化和成熟的障碍密切相关，通过 WNT/β-catenin 信号通路，这将最终导致轴突髓鞘形成不足。