Inhibition of S100A4 decreases neurotoxic astrocyte reactivity and attenuates neuropathic pain via the TLR4/NF-κB pathway in a rat model of spinal nerve ligation

S100A4 participates in inflammation and immune reactions in the central nervous system and is involved in the pathogenesis of multiple neurological disorders. It can affect the functions of astrocytes, microglia, infiltrating cells and neurons and further modulates neuronal plasticity and survival in the central nervous system. However, its impact on astrocyte phenotypes and neuropathic pain and the intrinsic mechanisms involved remain poorly understood. Here, we showed that S100A4 was markedly upregulated after spinal nerve ligation and was mainly expressed in neurons in the spinal dorsal horn. Transcriptional inhibition of S100A4 with niclosamide attenuated neuropathic pain after surgery. We found that astrocytes differentiated into C3-positive reactive populations, so-called neurotoxic (A1) astrocytes and identified differentially expressed genes and specific molecular expression signatures after ligation. Neurotoxic astrocyte reactivity is regulated by exogenous S100A4 in vitro, and targeted inhibition of S100A4 suppresses neurotoxic astrocyte proliferation in rats. Finally, we reported that TLR4/NF-κB signaling pathway is a downstream of S100A4 activation, and that specific depletion this pathway suppresses deleterious A1 astrocyte activation and further attenuates the development and maintenance of neuropathic pain after spinal nerve ligation. Thus, S100A4 in neurons plays a key role in neurotoxic astrocyte reactivity and can be targeted for treatment to prevent and alleviate neuropathic pain.