Inhibition of NFAT5-Dependent Astrocyte Swelling Alleviates Neuropathic Pain

Astrocyte swelling is implicated in various neurological disorders. However, whether astrocyte swelling contributes to neuropathic pain remains elusive. This study elucidates the pivotal role of the nuclear factor of activated T-cells 5 (NFAT5) emerges as a master regulator of astrocyte swelling in the spinal dorsal horn (SDH) during neuropathic pain. Despite the ubiquitous expression of NFAT5 protein in SDH cell types, it selectively induces swelling specifically in astrocytes, not in microglia. Mechanistically, NFAT5 directly controls the expression of the water channel aquaporin-4 (AQP4), a key regulator exclusive to astrocytes. Additionally, aurora kinase B (AURKB) orchestrates NFAT5 phosphorylation, enhancing its protein stability and nuclear translocation, thereby regulating AQP4 expression. The findings establish NFAT5 as a crucial regulator for neuropathic pain through the modulation of astrocyte swelling. The AURKB-NFAT5-AQP4 pathway in astrocytes emerges as a potential therapeutic target to combat neuropathic pain. Peripheral nerve injury induces morphological changes in spinal dorsal horn astrocytes, characterized by significant cell swelling, a prominent pathological feature in the context of neuropathic pain. The NFAT5 signaling pathway plays a crucial role in astrocyte swelling after peripheral nerve injury. AURKB mediates NFAT5 phosphorylation, promotes NFAT5 translocation into the nucleus and protects it from degradation. The nuclear NFAT5 further stimulates the transcription and expression of AQP4, which subsequently leads to astrocyte swelling and contributes to the development of neuropathic pain.image