中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (11): 3287-3301.doi: 10.4103/NRR.NRR-D-23-01256

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

药物性靶向cGAS/STING/NF-κB通路调节脊髓损伤后的小胶质细胞极化

  

  • 出版日期:2025-11-15 发布日期:2025-02-25
  • 基金资助:
    这项工作得到了国家自然科学基金（82071387，81971172），浙江省自然科学基金（LY22H090012）和温州市基础性科研项目（Y20220923）的支持。

Pharmacological targeting cGAS/STING/NF-κB axis by tryptanthrin induces microglia polarization toward M2 phenotype and promotes functional recovery in a mouse model of spinal cord injury

Ziwei Fan1, 2, #, Mengxian Jia1, 2, #, Jian Zhou1, 2, Zhoule Zhu1, 2, Yumin Wu1, 2, Xiaowu Lin1, 2, Yiming Qian2 , Jiashu Lian1, 2, Xin Hua2, 3, Jianhong Dong2 , Zheyu Fang2, 3, Yuqing Liu2 , Sibing Chen2 , Xiumin Xue2 , Juanqing Yue4 , Minyu Zhu1 , Ying Wang5, *, Zhihui Huang1, 2, *, Honglin Teng1, *   

  1. 1 Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China;  2 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China;  3 Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China;  4 Department of Pathology, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province, China;  5 Department of Clinical Research Center, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province, China
  • Online:2025-11-15 Published:2025-02-25
  • Contact: Ying Wang, PhD, nancywangying@163.com; Zhihui Huang, PhD, huang0069@hznu.edu.cn; Honglin Teng, MD, tenghonglin@wzhospital.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82071387 (to HT), 81971172 (to YW); the Natural Science Foundation of Zhejiang Province, China, No. LY22H090012 (to HT); and the Basic Research Project of Wenzhou City, China, No. Y20220923 (to MZ).

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摘要：

脊髓损伤后小胶质细胞的M1/M2表型转变在脊髓损伤继发性损伤阶段神经炎症的调节中发挥着重要作用。如何调控脊髓损伤后小胶质细胞的M1促炎表型向M2抗炎表型极化转换显得至关重要。色胺酮具有抗炎的生物学功能，但其在脊髓损伤 中的作用及其潜在的分子机制尚不清楚。实验发现色胺酮在体外促进小胶质细胞极化为 M2 表型，从而抑制了小胶质细胞源性炎症。其次，色胺酮通过抑制 cGAS/STING/NF-κB 通路活性来促进小胶质细胞的 M2 极化。有趣的是，袊发现，色胺酮靶向cGAS/STING/NF-κB通路能使小胶质细胞在脊髓损伤后从M1表型转变为M2表型，最终抑制神经元的丢失，促进脊髓损伤后的组织修复和功能恢复。最后，基于条件共培养系统，实验发现用色胺酮处理的小胶质细胞抑制了内质网应激相关的神经元凋亡。综上所述，色胺酮以 cGAS/STING/NF-κB 通路为靶点，可通过调节小胶质细胞极化至 M2 表型，减轻小胶质细胞源性神经炎症并促进脊髓损伤 后的功能恢复。

https://orcid.org/0000-0003-2121-7025 (Ying Wang); https://orcid.org/0000-0002-1927-0946 (Zhihui Huang); 
https://orcid.org/0000-0002-4745-892X (Honglin Teng)

Abstract: The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury. Regulation of shifting microglia polarization from M1 (neurotoxic and proinflammatory type) to M2 (neuroprotective and anti-inflammatory type) after spinal cord injury appears to be crucial. Tryptanthrin possesses an anti-inflammatory biological function. However, its roles and the underlying molecular mechanisms in spinal cord injury remain unknown. In this study, we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro. Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway. Additionally, we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury, inhibited neuronal loss, and promoted tissue repair and functional recovery in a mouse model of spinal cord injury. Finally, using a conditional co-culture system, we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress–related neuronal apoptosis. Taken together, these results suggest that by targeting the cGAS/STING/NF-κB axis, tryptanthrin attenuates microglia–derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.

Key words: cGAS/STING, functional recovery, microglia, neuroinflammation, neuroprotection, nuclear factor-κB, polarization, spinal cord injury, tryptanthrin