Pseudomonas aeruginosa (P. aeruginosa) keratitis, a worldwide leading cause of corneal perforation and blindness, which is associated with contact lens usage. Increasing evidence has indicated that pyroptosis, a novel proinflammatory programmed cell death, is linked with ocular diseases, little is known about the role of noncanonical pyroptosis in microbial keratitis. Here, we first indicated the involvement of noncanonical pyroptosis in P. aeruginosa keratitis and investigated whether wedelolactone (WDL), a major active component of Eclipta prostrate known to target caspase-11, could alleviate P. aeruginosa keratitis development. We found the expression of caspase-4/5/11 and cleaved GSDMD in corneas of P. aeruginosa keratitis patients, animal models and lipopolysaccharide (LPS)-induced primary cultured human corneal keratocytes (piHCKs) were increased. Combining ciprofloxacin with WDL significantly ameliorated the severity of P. aeruginosa keratitis, as manifested by decreased inflammatory responses and reduced corneal epithelial defects. Consistent with these findings, WDL also dose-dependently alleviated LPS-induced noncanonical pyroptosis by reversing the increased expression of caspase-4/5 and GSDMD in piHCKs. In summary, our results demonstrated that by targeting the activation of caspase-4/5/11, wedelolactone inhibited the development of P. aeruginosa keratitis and suppressed the release of proinflammatory cytokines. Wedelolactone may be a promising anti-inflammatory candidate to combat P. aeruginosa keratitis.

铜绿假单胞菌( P. aeruginosa ) 角膜炎是世界范围内角膜穿孔和失明的主要原因，与隐形眼镜的使用有关。越来越多的证据表明，细胞焦亡是一种新型的促炎程序性细胞死亡，与眼部疾病有关，但对非典型焦亡在微生物角膜炎中的作用知之甚少。在这里，我们首先指出了铜绿假单胞菌角膜炎中非典型细胞焦亡的参与，并研究了旱草内酯 (WDL)（一种已知以 caspase-11 为靶点的旱旱莲的主要活性成分）是否可以缓解铜绿假单胞菌角膜炎的发展。我们发现 caspase-4/5/11 和 Cleaved GSDMD 在角膜中的表达铜绿假单胞菌角膜炎患者、动物模型和脂多糖 (LPS) 诱导的原代培养的人角膜角膜细胞 (piHCK) 增加。环丙沙星与 WDL 联合使用可显着改善铜绿假单胞菌角膜炎的严重程度，表现为炎症反应减少和角膜上皮缺损减少。与这些发现一致，WDL 还通过逆转 piHCK 中 caspase-4/5 和 GSDMD 的表达增加，剂量依赖性地减轻 LPS 诱导的非经典细胞焦亡。总之，我们的结果表明，通过靶向激活 caspase-4/5/11，wedelolactone 抑制了铜绿假单胞菌的发育角膜炎并抑制促炎细胞因子的释放。Wedelolactone 可能是对抗铜绿假单胞菌角膜炎的有希望的抗炎候选物。