TLR9 in satellite glial cells promotes paclitaxel-induced neuropathic pain by reducing Kir4.1 transcription through histone methylation activation.

Chemotherapy-induced neuropathic pain (CINP), commonly induced by paclitaxel (PTX), is a debilitating side effect that often leads to the discontinuation of cancer treatment. Despite its significant impact on patients' quality of life, the mechanisms underlying CINP remain poorly understood. Recent studies have suggested that immune system activation, particularly through Toll-like receptor 9 (TLR9), plays a crucial role in the development of neuropathic pain. In this study, we investigated the involvement of TLR9 in PTX-induced CINP, with a focus on satellite glial cells (SGCs) in the dorsal root ganglion (DRG). We found that TLR9 expression was significantly upregulated in SGCs following PTX treatment, and its activation contributed to the downregulation of Kir4.1 (potassium inwardly rectifying channel, subfamily J, member 10), a key potassium channel that regulates neuronal excitability. This process was mediated through histone methylation, involving the methyltransferase G9a and the NF-κB signaling pathway. Inhibition of TLR9 or knockdown of its expression alleviated PTX-induced pain behaviors while inhibiting G9a restored Kir4.1 function and reduced pain. These findings suggest that TLR9 and its downstream signaling pathways, including G9a-mediated histone modification, play a critical role in the development of CINP. Targeting TLR9 and histone methylation may provide novel therapeutic strategies for managing CINP and improving cancer treatment outcomes.