289 Sciatic Nerve Stimulation Modulates DRG Satellite Glial Cell Polarization and Alleviates Neuropathic Pain

INTRODUCTION: Satellite glial cells (SGCs) in the dorsal root ganglia (DRG) play a pivotal role in the formation of neuropathic pain (NP). Sciatic nerve stimulation (SNS) neuromodulation was shown to alleviate NP and reduce neuroinflammation. However, the mechanisms underlying SNS in DRG remain unclear. We hypothesized that following nerve injury, activated SGCs possessed distinct inflammatory and anti-inflammatory phenotypes, that we termed S1 and S2, akin to A1 and A2 astrocytes, respectively. METHODS: L5 nerve root ligation (NRL) NP rats were studied. Ipsilateral SNS was performed on 1 day after NRL. Behavioral tests were performed to assess pain phenotypes. NanoString Ncounter technology was used to explore the differentially expressed genes. S1 SGCs were characterized in vitro and in vivo. The histochemical alterations of DRG SGCs, macrophages, and neurons were examined in vivo on post-injury day 8. RESULTS: SNS alleviated pain and thermal hypersensitivity in NRL rats. We found that SGCs possessed distinct inflammatory and anti-inflammatory phenotypes, which shared common markers C3 and S100A10 with A1 and A2 astrocytes, respectively. S1 SGCs were neurotoxic, leading to synapse loss and neuronal death. NP rats showed a polarization shift toward S1-polarized SGCs. Mechanistically, NRL induced reciprocal activation of S1 SGCs and M1 macrophages mediated by IL-6, CCL3, TNF-?, and the HIF-1α-NF-κB pathways. SNS suppressed S1 polarization and induced S2 polarization, thereby alleviating NP and DRG neuroinflammation. CONCLUSIONS: Our findings establish S1/S2 SGC polarization as an essential pathomechanism in the gliopathic alterations in NP, which can be modulated by SNS.