Fibroblast Growth Factor 8 Suppresses Neurotoxic Astrocytes and Alleviates Neuropathic Pain via Spinal FGFR3 Signaling.
10.1007/s12264-025-01533-x
- Author:
Huizhu LIU
1
;
Lanxing YI
1
;
Guiling LI
1
;
Kangli WANG
1
;
Hongsheng WANG
2
;
Yuqiu ZHANG
3
;
Benlong LIU
4
Author Information
1. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
2. Department of Traditional Chinese Medicine, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China.
3. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China. yuqiuzhang@fudan.edu.cn.
4. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China. liu_b@fudan.edu.cn.
- Publication Type:Journal Article
- Keywords:
FGF8;
FGFR3 signaling;
Microglia–astrocyte interaction;
Neuropathic pain;
Reactive astrocytes;
Spinal dorsal horn
- MeSH:
Animals;
Astrocytes/drug effects*;
Neuralgia/pathology*;
Receptor, Fibroblast Growth Factor, Type 3/metabolism*;
Signal Transduction/physiology*;
Male;
Mice;
Microglia/drug effects*;
Fibroblast Growth Factor 8/pharmacology*;
Mice, Inbred C57BL;
Hyperalgesia/drug therapy*;
Spinal Cord/drug effects*;
Complement C3/metabolism*;
Spinal Cord Dorsal Horn/metabolism*
- From:
Neuroscience Bulletin
2025;41(12):2218-2232
- CountryChina
- Language:English
-
Abstract:
Astrocytes in the spinal dorsal horn (SDH) exhibit diverse reactive phenotypes under neuropathic conditions, yet the mechanisms driving this diversity and its implications in chronic pain remain unclear. Here, we report that spared nerve injury (SNI) induces marked upregulation of both complement component 3 (C3⁺, A1-like) and S100 calcium-binding protein A10 (S100A10⁺, A2-like) astrocyte subpopulations in the SDH, with elevated microglial cytokines including interleukin-1α, tumor necrosis factor-α, and complement component 1q. Transcriptomic, immunohistochemical, and Western blot analyses reveal co-activation of multiple reactive astrocyte states over a unidirectional shift toward an A1-like phenotype. Fibroblast growth factor 8 (FGF8), a neuroprotective factor via FGFR3, mitigated microglia-induced C3⁺ astrocyte reactivity in vitro and suppressed spinal C3 expression and mechanical allodynia following intrathecal administration in SNI mice. These findings reveal a microglia-astrocyte signaling axis that promotes A1 reactivity and position FGF8 as a promising therapeutic candidate for neuropathic pain by modulating astrocyte heterogeneity.
