Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune-mediated demyelinating diseases.
Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune-mediated demyelinating diseases.
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作者：
Stone S;Wu S;Jamison S;Durose W;Pallais JP;Lin W
内质网应激（endoplasmic reticulum，ER）和未折叠蛋白反应（unfolded protein response，UPR）通过调节少突胶质细胞的活力，在免疫介导的脱髓鞘疾病中发挥重要作用，包括多发性硬化（multiple sclerosis，MS）及其动物模型实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis，EAE）。我们以前的研究表明，UPR的PERK分支的激活保护年轻的、发育中的小鼠中的髓鞘化少突胶质细胞免受ER应激，所述小鼠在CNS中表达IFN-γ，其是MS和EAE中的关键促炎细胞因子。几项研究还表明，PERK激活保留少突胶质细胞的活力和功能，保护小鼠免受EAE。虽然有证据表明在正常和疾病条件下少突胶质细胞中UPR的ATF 6 α分支活化，但在免疫介导的脱髓鞘疾病中ATF 6 α活化对少突胶质细胞的影响仍然未知。在此，我们发现在正常条件下，ATF 6 α缺陷对少突胶质细胞没有影响。有趣的是，我们发现ATF 6 α缺乏加剧了ER应激诱导的髓鞘生成少突胶质细胞死亡和随后IFN-γ表达小鼠发育中CNS中的髓鞘丢失。此外，我们发现ATF 6 α缺乏增加了EAE的严重程度，加重了EAE诱导的少突胶质细胞丢失和脱髓鞘，而不影响炎症。因此，这些数据表明，在免疫介导的脱髓鞘疾病中，ATF 6 α活化对少突胶质细胞具有保护作用。
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play a critical role in immune-mediated demyelinating diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), by regulating the viability of oligodendrocytes. Our previous studies show that activation of the PERK branch of the UPR protects myelinating oligodendrocytes against ER stress in young, developing mice that express IFN-γ, a key pro-inflammatory cytokine in MS and EAE, in the CNS. Several studies also demonstrate that PERK activation preserves oligodendrocyte viability and function, protecting mice against EAE. While evidence suggests activation of the ATF6α branch of the UPR in oligodendrocytes under normal and disease conditions, the effects of ATF6α activation on oligodendrocytes in immune-mediated demyelinating diseases remain unknown. Herein, we showed that ATF6α deficiency had no effect on oligodendrocytes under normal conditions. Interestingly, we showed that ATF6α deficiency exacerbated ER stressed-induced myelinating oligodendrocyte death and subsequent myelin loss in the developing CNS of IFN-γ-expressing mice. Moreover, we found that ATF6α deficiency increased EAE severity and aggravated EAE-induced oligodendrocyte loss and demyelination, without affecting inflammation. Thus, these data suggest the protective effects of ATF6α activation on oligodendrocytes in immune-mediated demyelinating diseases.
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