Paeoniflorin inhibited nod‐like receptor protein‐3 inflammasome and NF‐κB‐mediated inflammatory reactions in diabetic foot ulcer by inhibiting the chemokine receptor CXCR2

Abstract Diabetic foot ulcer (DFU) is an invariably common complication of diabetes, characterized by delayed wound healing process and increased inflammation. Evidence has indicated that paeoniflorin exerts an anti‐inflammatory effect in diabetic retinopathy. The current work was aimed to investigate the effect of paeoniflorin on inflammation and wound healing in DFU. DFU rat models by streptozotocin and skin biopsy punch, as well as high glucose‐treated human immortalized keratinocytes (HaCaT) were established. Levels of blood glucose, wound contraction and proinflammatory cytokine were detected after paeoniflorin administration. Several essential targets associated with the NF‐κB and Nod‐like receptor protein‐3 (NLRP3) signaling pathways were examined. Results showed markedly down‐regulation of interleukin (IL)‐1β, IL‐18 and tumor necrosis factor‐alpha in paeoniflorin‐treated DFU rats. Paeoniflorin decreased the expression levels of chemokine receptor CXCR2, nuclear NF‐κB and p‐IκB (Ser36), as well as increased IκB level. Histological analysis and immunostaining showed lower inflammatory cells with decreased NLRP3 and cleaved caspase‐1 levels following paeoniflorin treatment. Further in vitro evidence confirmed that paeoniflorin efficiently inhibited NLRP3 and NF‐κB‐mediated inflammation in DFU by inhibiting CXCR2. These findings are suggestive of greatly attenuated wound inflammation and better wound healing in paeoniflorin‐treated DFU rats. Our study demonstrates that paeoniflorin is a potential therapeutic agent for DFU.