Department of Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
School of Medicine, South China University of Technology, Guangzhou, 510006, China.
Mol Neurobiol. 2021 Dec;58(12):6552-6576. doi: 10.1007/s12035-021-02568-7. Epub 2021 Sep 28.
Microglia activation and associated inflammation are implicated in the periventricular white matter damage (PWMD) in septic postnatal rats. This study investigated whether melatonin would mitigate inflammation and alleviate the axonal hypomyelination in the corpus callosum in septic postnatal rats. We further explored if this might be related to the modulation of microglial polarization from M1 phenotype to M2 through the JAK2/STAT3/telomerase pathway. We reported here that indeed melatonin not only can it reduce the neurobehavioral disturbances in LPS-injected rats, but it can also dampen microglia-mediated inflammation. Thus, in LPS + melatonin group, the expression of proinflammatory mediators in M1 phenotype microglia was downregulated. As opposed to this, M2 microglia were increased which was accompanied by upregulated expression of anti-inflammatory mediators along with telomerase reverse transcriptase or melatonin receptor 1(MT1). In parallel to this was decreased NG2 expression but increased expression of myelin and neurofilament proteins. Melatonin can improve hypomyelination which was confirmed by electron microscopy. In vitro in primary microglia stimulated by LPS, melatonin decreased the expression of proinflammatory mediators significantly; but it increased the expression of anti-inflammatory mediators. Additionally, the expression levels of p-JAK2 and p-STAT3 were significantly elevated in microglia after melatonin treatment. Remarkably, the effect of melatonin on LPS-treated microglia was blocked by melatonin receptor, JAK2, STAT3 and telomerase reverse transcriptase inhibitors, respectively. Taken together, it is concluded that melatonin can attenuate PWMD through shifting M1 microglia towards M2 via MT1/JAK2/STAT3/telomerase pathway. The results suggest a new therapeutic strategy whereby melatonin may be adopted to convert microglial polarization from M1 to M2 phenotype that would ultimately contribute to the attenuation of PWMD.
小胶质细胞的激活和相关炎症反应被认为与败血症新生大鼠的脑室周围白质损伤（PWMD）有关。本研究旨在探讨褪黑素是否能减轻炎症反应并缓解败血症新生大鼠胼胝体的轴突脱髓鞘。我们进一步探讨了这是否与通过 JAK2/STAT3/端粒酶通路调节小胶质细胞从 M1 表型向 M2 极化有关。我们在此报告，褪黑素不仅可以减轻 LPS 注射大鼠的神经行为障碍，还可以抑制小胶质细胞介导的炎症反应。因此，在 LPS+褪黑素组中，M1 表型小胶质细胞中促炎介质的表达下调。与此相反，M2 小胶质细胞增加，同时抗炎介质以及端粒酶逆转录酶或褪黑素受体 1（MT1）的表达上调。与之平行的是 NG2 表达降低，但髓鞘和神经丝蛋白的表达增加。电镜证实，褪黑素可改善脱髓鞘。在 LPS 刺激的原代小胶质细胞中，褪黑素显著降低了促炎介质的表达；但它增加了抗炎介质的表达。此外，褪黑素处理后小胶质细胞中 p-JAK2 和 p-STAT3 的表达水平显著升高。值得注意的是，褪黑素对 LPS 处理的小胶质细胞的作用分别被褪黑素受体、JAK2、STAT3 和端粒酶逆转录酶抑制剂阻断。综上所述，褪黑素通过 MT1/JAK2/STAT3/端粒酶通路将 M1 小胶质细胞向 M2 转化，从而减轻 PWMD。结果表明，褪黑素可能通过将小胶质细胞从 M1 表型转化为 M2 表型来减轻 PWMD，这最终有助于减轻 PWMD。
