Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis
Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis
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外周骨髓细胞中的 Gasdermin D 驱动实验性自身免疫性脑脊髓炎的神经炎症
DOI：
10.1084/jem.20190377
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发表时间：
2019-11-01
影响因子：
15.3
通讯作者：
Yang, Shuo
中科院分区：
文献类型：
--
作者：
Li, Sheng;Wu, Yuqing;Yang, Shuo
NLRP3 炎性体对于 EAE 发病机制至关重要；然而，gasdermin D (GSDMD)（一种新发现的 NLRP3 炎性体下游的细胞焦亡刽子手）在 EAE 中的作用尚未明确。在这里，我们观察到 EAE 小鼠中枢神经系统中 GSDMD 蛋白的水平大大增强，尤其是血管周围区域。 GSDMD 是 EAE 发病机制所必需的，外周髓细胞中 GSDMD 的缺乏会损害免疫细胞向 CNS 的浸润，从而抑制神经炎症和脱髓鞘。此外，GSDMD的缺失降低了次级淋巴器官中T细胞的活化和分化，并阻止了T细胞浸润到EAE的CNS中。炎症体相关细胞因子的施用部分挽救了 GSDMD KO 小鼠中 EAE 发病机制的损害。总的来说，这些发现首次证明了 EAE 发病过程中外周骨髓细胞中 GSDMD 驱动神经炎症。
The NLRP3 inflammasome is critical for EAE pathogenesis; however, the role of gasdermin D (GSDMD), a newly identified pyroptosis executioner downstream of NLRP3 inflammasome, in EAE has not been well defined. Here, we observed that the levels of GSDMD protein were greatly enhanced in the CNS of EAE mice, especially near the areas surrounding blood vessels. GSDMD was required for the pathogenesis of EAE, and GSDMD deficiency in peripheral myeloid cells impaired the infiltration of immune cells into the CNS, leading to the suppression of neuroinflammation and demyelination. Furthermore, the loss of GSDMD reduced the activation and differentiation of T cell in the secondary lymphoid organs and prevented T cell infiltration into CNS of EAE. The administration of inflammasome-related cytokines partially rescued the impairment of pathogenesis of EAE in GSDMD KO mice. Collectively, these findings provide the first demonstration of GSDMD in peripheral myeloid cells driving neuroinflammation during EAE pathogenesis.