Department of Neurosurgery, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
Department of Genomic Medicine, Cleveland Clinic/Lerner Research Institute, Cleveland, OH, USA.
J Neuroinflammation. 2019 Feb 8;16(1):28. doi: 10.1186/s12974-019-1420-9.
Inappropriate contact between the immune system and the central nervous system is thought to be a cause of demyelination. We previously reported the ability of the class IV semaphorin, Semaphorin4A (Sema4A), to induce apoptosis in human oligodendrocytes; however, these results have yet to be translated to an in vivo setting. Importantly, HIV-associated neurocognitive disorder remains a significant complication for patients on combined anti-retroviral therapy, with white matter damage seen on MRI.
Human cerebrospinal fluid and serum was assayed for Sema4A using a Sema4A-specific ELISA. Wild-type mice were injected with Sema4A via stereotaxic infusion. Data was assessed for significance using unpaired t tests, comparing the corpus callosum of PBS-injected mice versus Sema4A-injected mice.
Here, we demonstrate elevated levels of Sema4A in the cerebrospinal fluid and serum of people with HIV infection. Furthermore, we demonstrate that direct injection of Sema4A into the corpus callosum of mice results in loss of myelin architecture and decreased myelin, concomitant with apoptosis of mature myelinating oligodendrocytes. Sema4A injection also causes increased activation of microglia.
Taken together, our data further establish Sema4A as a potentially significant mediator of demyelinating diseases and a direct connection between the immune system and oligodendrocytes.
免疫系统与中枢神经系统之间的不当接触被认为是脱髓鞘的一个原因。我们之前报道了第四类信号素 Semaphorin4A（Sema4A）诱导人少突胶质细胞凋亡的能力；然而，这些结果尚未转化为体内环境。重要的是，艾滋病毒相关神经认知障碍仍然是接受联合抗逆转录病毒治疗的患者的一个重大并发症，在 MRI 上可见到白质损伤。
使用 Sema4A 特异性 ELISA 检测人脑脊液和血清中的 Sema4A。通过立体定向输注向野生型小鼠注射 Sema4A。使用未配对的 t 检验评估数据的显著性，比较 PBS 注射小鼠和 Sema4A 注射小鼠的胼胝体。
在这里，我们证明了 HIV 感染者脑脊液和血清中 Sema4A 水平升高。此外，我们证明了将 Sema4A 直接注射到小鼠的胼胝体中会导致髓鞘结构丧失和髓鞘减少，同时成熟的髓鞘形成少突胶质细胞凋亡。Sema4A 注射还会导致小胶质细胞的激活增加。
总之，我们的数据进一步确立了 Sema4A 作为脱髓鞘疾病的潜在重要介质，以及免疫系统与少突胶质细胞之间的直接联系。
