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

• Published in: European journal of pharmacology Vol. 930; p. 175156
• Main Authors: Liang, Shuli, Yang, Zhongjin, Hua, Lei, Chen, Yanhong, Zhou, Yinghua, Ou, Yitao, Chen, Xiuhui, Yue, Hu, Yang, Xiangyu, Wu, Xinyi, Hu, Wenhui, Sun, Ping
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05-09-2022
• Subjects: Ciclopirox; IL-1β; Macrophage; Mitochondrial reactive oxygen species; NLRP3 inflammasome; Psoriasis; Mitochondrial reactive oxygen species; Psoriasis; NLRP3 inflammasome; IL-1β; Ciclopirox; Macrophage
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2022.175156

The maturation and secretion of interleukin-1β (IL-1β) 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 μM). Mechanistically, CPX upregulated peroxisome proliferator-activated receptor-γ coactivator-1α expression (by 82.7% at 5 μM and 87.5% at 10 μM) 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.
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•Ciclopirox inhibit NLRP3 inflammasome activation.•Ciclopirox upregulated PGC-1α expression to improve mitochondrial function.•Ciclopirox ameliorated inflammatory response in imiquimod-induced psoriasis mice.