2. Academic Validation
  3. 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

  • Cell Death Dis. 2022 Sep 2;13(9):759. doi: 10.1038/s41419-022-05202-z.
Lingting Jin  # 1 2 3,  Jingjing Zhang  # 2,  Xin Hua  # 2,  Xingxing Xu 2,  Jia Li 1,  Jiaojiao Wang 2,  Mianxian Wang 2,  Huitao Liu 2,  Haoyu Qiu 2,  Man Chen 2,  Xu Zhang 4,  Ying Wang 5,  Zhihui Huang 6 7 8
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2 School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
  • 3 School of Pharmacy, and Department of Neurosurgery of the Affiliated Hospital,, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China.
  • 4 Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. drzhangxu@live.cn.
  • 5 Clinical Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China. nancywangying@163.com.
  • 6 Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. huang0069@hznu.edu.cn.
  • 7 School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. huang0069@hznu.edu.cn.
  • 8 School of Pharmacy, and Department of Neurosurgery of the Affiliated Hospital,, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China. huang0069@hznu.edu.cn.
  • # Contributed equally.
PMID: 36055989 DOI: 10.1038/s41419-022-05202-z
Abstract

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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