S100A9 plays a role in neuropathic pain by regulating GPR153/Kcnk16 function in DRG neurons.

Abstract

Neuropathic pain, attributed to its intricate pathogenesis, remains challenging to treat effectively. This study delineates neuroimmune-glial cell interactions within the ganglia as a pivotal mechanism initiating nerve damage, thereby contributing to neuropathic pain. Utilizing a chronic constriction injury (CCI) mouse model, we explored the pro-inflammatory molecule S100A9, secreted by myeloid cells, in the context of neuropathic pain development. Our findings revealed an upregulation of S100A9 in the dorsal root ganglia (DRGs) of CCI mice, predominantly due to neutrophil infiltration. Notably, S100A9 knockout significantly mitigated mechanical pain hypersensitivity and inflammation induced by CCI. We further elucidated the role of S100A9 in mechanical pain hypersensitivity using inhibitors and recombinant S100A9 proteins. Transcriptome sequencing indicated that S100A9 potentially influenced neuropathic pain by modulating the expression of orphan G protein-coupled receptor 153 (GPR153) and potassium channel Kcnk16 on the DRG neuron membrane. Collectively, our research underscores the significant role of S100A9 in neuropathic pain pathogenesis and presents it as a promising therapeutic target. KEY INNOVATIONS.