Psoriasis is a common chronic autoinflammatory/autoimmune skin disease associated with elevated pro-inflammatory cytokines. The pivotal role of interleukin (IL)-1β and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathogenesis of psoriasis has been widely described. Accordingly, the suppression of NLRP3-dependent IL-1β release is a potential therapy for psoriasis. Repurposing marketed drugs is a strategy for identifying new inhibitors of NLRP3 inflammasome activation. Herein, chlorquinaldol (CQD), a historic antimicrobial agent used as a topical treatment for skin and vaginal infections, was found to have a distinct effect by inhibiting NLRP3 inflammasome activation at concentrations ranging from 2 to 6 μM. CQD significantly suppressed apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) oligomerization, NLRP3-ASC interaction, and pyroptosis in macrophages. The levels of cleaved IL-1β and caspase-1 were reduced by CQD in the cell lysates of macrophages, suggesting that CQD acted on upstream of pore formation in the cell membrane. Mechanistically, CQD reduced mitochondrial reactive oxygen species production but did not affect the nuclear factor-κB (NF-κB) pathway. Intraperitoneal administration of CQD (15 mg/kg) for 6 days was found to improve the skin lesions in the imiquimod-induced psoriatic mouse model (male C57BL/6 mice), while secretion of pro-inflammatory cytokines (IL-17 and IL-1β) and keratinocyte proliferation were significantly suppressed by CQD. In conclusion, CQD exerted inhibitory effects on NLRP3 inflammasome activation in macrophages and decreased the severity of psoriatic response in vivo. Such findings indicate that the repurposing of the old drug, CQD, is a potential pharmacological approach for the treatment of psoriasis and other NLRP3-driven diseases.

银屑病是一种常见的慢性自身炎症/自身免疫性皮肤病，与促炎细胞因子升高有关。白细胞介素 (IL)-1β 和核苷酸结合寡聚结构域样受体家族pyrin结构域蛋白 3 (NLRP3) 炎性体在银屑病发病机制中的关键作用已被广泛描述。因此，抑制 NLRP3 依赖性 IL-1β 释放是银屑病的潜在疗法。重新利用已上市药物是一种识别 NLRP3 炎症小体激活新抑制剂的策略。在此，氯喹那多(CQD)，一种历史悠久的抗菌剂，用作皮肤和阴道感染的局部治疗，通过在 2 至 6 μM 的浓度范围内抑制 NLRP3 炎性体激活，发现具有明显的效果。CQD 显着抑制含有半胱天冬酶募集结构域 (ASC) 寡聚化、NLRP3-ASC 相互作用和巨噬细胞焦亡的凋亡相关斑点样蛋白。CQD 降低了巨噬细胞裂解物中裂解的 IL-1β 和 caspase-1 的水平，表明 CQD 作用于细胞膜孔形成的上游。从机制上讲，CQD 减少了线粒体活性氧的产生，但不影响核因子-κB（NF-κB）途径。在咪喹莫特诱导的银屑病小鼠模型（雄性 C57BL/6 小鼠）中，腹腔内给予 CQD（15 mg/kg）6 天可改善皮肤损伤，同时分泌促炎细胞因子（IL-17 和 IL- CQD 显着抑制 1β) 和角质形成细胞增殖。总之，CQD 对巨噬细胞中 NLRP3 炎症小体的活化发挥抑制作用，并降低体内。这些发现表明，旧药 CQD 的再利用是治疗银屑病和其他 NLRP3 驱动疾病的潜在药理学方法。