Oxidative stress-triggered pyroptosis mediates Candida albicans susceptibility in diabetic foot

An accumulating trend of research demonstrates that diabetic patients are susceptible to skin infections with Candida albicans, but the mechanism still remains unclear. The intense oxidative stress (OS) responses were occurred in the lesion of diabetic mice footpads after C. albicans infection. Localised skin infections would lead to more severe complications while the severity of the condition worsens or the inadequate treatment. Notably, in this study, through the investigation of murine diabetic footpad C. albicans infection model and molecular biotechnology, including histopathological staining, immunofluorescence (IF) staining, quantitative real-time PCR (qPCR), western blot (WB), flow cytometry (FCM), sandwich enzyme-linked immunosorbent assay (ELISA) assays, we found that intense OS responses in the footpad tissue not only mediated the activation of NF-κB protein complex, but also triggered downstream pyroptosis and apoptosis through NLRP3 inflammasome, which is one of the potential reasons for the severe condition of infectious skin injuries in diabetic mice. Caspase-1, a classical signal pathway protein in pyroptosis, could promote pore formation on cell membranes and the release of the cytokine after NLRP3 inflammasome activation. With intense immune-inflammatory responses, the organism also stimulates immune organs such as the spleen and lymph nodes to produce negative feedback regulation and generate CD4⁺CD25⁺Foxp3⁺ Treg cells to rectify the process. Therefore, combined with the results of this work, it is possible to design and screen relevant drugs for NLRP3 inflammasomes as core targets to keep the OS response at a low level in the footpad tissues.