Astrocytic SARM1 promotes neuroinflammation and axonal demyelination in experimental autoimmune encephalomyelitis through inhibiting GDNF signaling.
Astrocytic SARM1 promotes neuroinflammation and axonal demyelination in experimental autoimmune encephalomyelitis through inhibiting GDNF signaling.
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星形细胞Sarm1通过抑制GDNF信号通路促进实验性自身免疫性脑脊髓炎的神经炎症和轴索脱髓鞘。
DOI：
10.1038/s41419-022-05202-z
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发表时间：
2022-09-02
影响因子：
9
通讯作者：
Huang, Zhihui
中科院分区：
文献类型：
--
作者：
Jin, Lingting;Zhang, Jingjing;Hua, Xin;Xu, Xingxing;Li, Jia;Wang, Jiaojiao;Wang, Mianxian;Liu, Huitao;Qiu, Haoyu;Chen, Man;Zhang, Xu;Wang, Ying;Huang, Zhihui
星形胶质细胞是中枢神经系统(CNS)先天免疫反应的重要组成部分，参与多发性硬化症(MS)等中枢神经系统疾病的炎症和神经毒性反应。最近的研究表明，Sarm1在轴突变性和炎症中起着关键作用。然而，星形细胞Sarm1在多发性硬化症中的具体作用仍不清楚。在此，我们建立了小鼠实验性自身免疫性脑脊髓炎(EAE)的MS模型，发现Sarm1在EAE小鼠脊髓的星形胶质细胞中表达上调。此外，条件性基因敲除星形细胞Sarm1(SARM1GFAP-CKO小鼠、SARM1Aldh1L1-CKO小鼠)延缓了EAE的发病，减轻了炎性浸润，抑制了脱髓鞘和神经元死亡。Sarm1−/−星形胶质细胞表达胶质细胞源性神经营养因子。Western印迹和免疫染色进一步证实SARM1GFAP-CKO EAE小鼠脊髓星形胶质细胞GDNF表达上调。有趣的是，链脲佐菌素(STZ，一种用于下调GDNF的药物)治疗下调GDNF，使SARM1GFAP-CKO EAE小鼠的缺陷恶化。这些结果证实了星形细胞Sarm1通过抑制GDNF的表达促进EAE的神经炎症和轴索脱髓鞘，揭示了Sarm1/GDNF信号在EAE中的新作用，为MS的治疗提供了新的治疗思路。
Astrocytes are important components of the innate immune response in the central nervous system (CNS), involving in the inflammatory and neurotoxic responses that occur in CNS diseases, such as multiple sclerosis (MS). Recent studies have shown that SARM1 plays a critical role in axonal degeneration and inflammation. However, the detailed role of astrocytic SARM1 in MS remains unclear. Here, we established the MS model of mice - experimental autoimmune encephalomyelitis (EAE) and found that SARM1 was upregulated in astrocytes of the spinal cords of EAE mice. Moreover, conditional knockout of astrocytic SARM1 (SARM1GFAP-CKO mice, SARM1Aldh1L1-CKO mice) delayed EAE with later onset, alleviated the inflammatory infiltration, and inhibited the demyelination and neuronal death. Mechanically, RNA-seq revealed that the expression of glial-derived neurotrophic factor (GDNF) was upregulated in SARM1−/− astrocytes. Western blot and immunostaining further confirmed the upregulation of GDNF in spinal cord astrocytes of SARM1GFAP-CKO EAE mice. Interestingly, the downregulation of GDNF by streptozotocin (STZ, a drug used to downregulate GDNF) treatment worsened the deficits of SARM1GFAP-CKO EAE mice. These findings identify that astrocytic SARM1 promotes neuroinflammation and axonal demyelination in EAE by inhibiting the expression of GDNF, reveal the novel role of SARM1/GDNF signaling in EAE, and provide new therapeutic ideas for the treatment of MS.
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DOI：
10.1038/s41583-020-0269-3
发表时间：
2020-04
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Coleman MP;Höke A
通讯作者：
Höke A
DOI：
10.1016/s1474-4422(17)30299-5
发表时间：
2017-11
期刊：
The Lancet. Neurology
影响因子：
--
作者：
GBD 2015 Neurological Disorders Collaborator Group
通讯作者：
GBD 2015 Neurological Disorders Collaborator Group
影响因子：
9.9
作者：
Lublin FD;Reingold SC;Cohen JA;Cutter GR;Sørensen PS;Thompson AJ;Wolinsky JS;Balcer LJ;Banwell B;Barkhof F;Bebo B Jr;Calabresi PA;Clanet M;Comi G;Fox RJ;Freedman MS;Goodman AD;Inglese M;Kappos L;Kieseier BC;Lincoln JA;Lubetzki C;Miller AE;Montalban X;O'Connor PW;Petkau J;Pozzilli C;Rudick RA;Sormani MP;Stüve O;Waubant E;Polman CH
通讯作者：
Polman CH
影响因子：
11.2
作者：
Peterson, JW;Bö, L;Trapp, BD
通讯作者：
Trapp, BD
影响因子：
5.4
作者：
Glatigny, Simon;Bettelli, Estelle
通讯作者：
Bettelli, Estelle