Huizhu Liu1  · Lanxing Yi1  · Guiling Li1  · Kangli Wang1  · Hongsheng Wang2  · Yuqiu Zhang1  · Benlong Liu1

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

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.

Keywords

Reactive astrocytes; FGF8; FGFR3 signaling; Microglia–astrocyte interaction; Neuropathic pain; Spinal dorsal horn

[SpringerLink]