Nav1.8 in keratinocytes contributes to ROS-mediated inflammation in inflammatory skin diseases

Reactive oxygen species (ROS)-activated proinflammatory signals in keratinocytes play a crucial role in the immunoregulation of inflammatory skin diseases, including rosacea and psoriasis. Nav1.8 is a voltage-gated sodium ion channel, and its abnormal expression in the epidermal layer contributes to pain hypersensitivity in the skin. However, whether and how epidermal Nav1.8 is involved in skin immunoregulation remains unclear. This study was performed to identify the therapeutic role of Nav1.8 in inflammatory skin disorders. We found that Nav1.8 expression was significantly upregulated in the epidermis of rosacea and psoriasis skin lesions. Nav1.8 knockdown ameliorated skin inflammation in LL37-and imiquimod-induced inflammation mouse models. Transcriptome sequencing results indicated that Nav1.8 regulated the expression of pro-inflammatory mediators (IL1β and IL6) in keratinocytes, thereby contributing to immune infiltration in inflammatory skin disorders. In vitro, tumor necrosis factor alpha (TNFα), a cytokine that drives the development of various inflammatory skin disorders, increased Nav1.8 expression in keratinocytes. Knockdown of Nav1.8 eliminated excess ROS production, thereby attenuating the TNFα-induced production of inflammatory mediators; however, a Nav1.8 blocker did not have the same effect. Mechanistically, Nav1.8 reduced superoxide dismutase 2 (SOD2) activity by directly binding to SOD2 to prevent its deacetylation and mitochondrial localization, subsequently inducing ROS accumulation. Collectively, our study describes a central role for Nav1.8 in regulating pro-inflammatory responses in the skin and indicates a novel therapeutic strategy for rosacea and psoriasis.