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 th...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.展开更多
基金supported by the Science and Technology Innovation(STI)2030-Major Projects(2025ZD0214900-02 and 2021ZD0203200-05)the National Natural Science Foundation of China(82130032)+1 种基金the Natural Science Foundation of Shanghai(24ZR1413900 and 25ZR1402460)and the China Postdoctoral Science Foundation(2021M690685).
文摘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.
