The effect of Staphylococcus aureus targeting ROS-dependent mitochondrial damage activating NLRP10 in inducing skin and soft tissue infection.

Mitochondrial dysfunction and reactive oxygen species (ROS) accumulation are central to the pathogenesis of Staphylococcus aureus-induced skin and soft tissue infections (SSTIs). NLRP10 has recently been identified as a key regulator of mitochondrial homeostasis and ROS dynamics. To investigate its regulatory role, we established an in vivo model of methicillin-resistant Staphylococcus aureus (MRSA)-induced SSTIs, which demonstrated significant skin lesions, necrosis, inflammatory infiltration, elevated ROS and LDH levels, decreased NAD+/NADH ratio and ATP content, enhanced apoptosis, and upregulated expression of Cleaved caspase-3, Bax, NLRP10, Cleaved caspase-1, ASC, and phosphorylated NF-κB p65. In vitro, using human primary keratinocytes, NLRP10 knockdown was found to exacerbate MRSA-induced mitochondrial ROS increase, loss of membrane potential, and apoptosis, while attenuating LDH release, ATP depletion, and the secretion of IL-1β/IL-18, as well as reducing the expression of Cleaved caspase-1, ASC, and phosphorylated NF-κB p65. Conversely, NLRP10 overexpression combined with the mitochondrial antioxidant MitoQ alleviated mitochondrial damage and apoptosis but significantly enhanced inflammasome activation and NF-κB pathway signaling. These findings collectively demonstrate that NLRP10 mediates its regulatory effects on Staphylococcus aureus-induced SSTIs through targeting ROS-driven mitochondrial dysfunction.