Ciclopirox inhibits NLRP3 inflammasome activation via protecting mitochondria and ameliorates imiquimod-induced psoriatic inflammation in mice

The maturation and secretion of interleukin-18 (IL-18) mediated by NLRP3 inflammasome activation plays an important role in the progression of many inflammatory diseases. Inhibition of NLRP3 inflammasome activation may be a promising strategy to treat these inflammation-driven diseases, such as psoriasis. As a broad-spectrum antifungal agent, ciclopirox (CPX) is widely used in the treatment of dermatomycosis. Although CPX has been reported to have anti-inflammatory effects in many studies, there has been little research into its underlying mechanisms. In our study, CPX reduced lipopolysaccharide (LPS)/nigericin-induced NLRP3 inflammasome activation (IC50: 1.684 mu M). Mechanistically, CPX upregulated peroxisome proliferator-activated receptor-gamma coactivator-1 alpha expression (by 82.7% at 5 mu M and 87.5% at 10 mu M) to protect mitochondria. Our studies showed that CPX reduced mitochondrial reactive oxygen species production, increased mitochondrial membrane potential, elevated mitochondrial biosynthesis, and up-regulated intracellular adenosine triphosphate level. Furthermore, treatment with CPX promoted the up-regulation of mRNA expression, which involved mitochondrial biosynthesis (NRF1, NRF2, TFAM) and antioxidation (SOD1 and CAT). In addition, CPX ameliorated inflammatory response in imiquimod-induced psoriasis mice. This study provides a potential pharmacological mechanism for CPX to treat psoriasis and other NLRP3-driven inflammatory diseases.

Automated summary

In this study, ciclopirox (CPX) was found to inhibit the activation of NLRP3 inflammasome by upregulating the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha. CPX also reduced mitochondrial reactive oxygen species production, increased mitochondrial membrane potential, elevated mitochondrial biosynthesis, and up-regulated intracellular adenosine triphosphate level, leading to its anti-inflammatory effects. In addition, CPX showed therapeutic effects in a psoriasis mouse model.