Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang University, Hangzhou 310058, Zhejiang, China.
Int Immunopharmacol. 2021 Mar;92:107358. doi: 10.1016/j.intimp.2020.107358. Epub 2021 Jan 25.
INF39 is a nontoxic, irreversible, acrylate-based NLRP3 inhibitor and a further optimization of ethyl 2-((2-chlorophenyl) hydroxyl) methyl) acrylate (INF4E). However, the detail mechanism and the direct target of its anti-inflammatory activity is not clear. Here, we show that INF39 is a specific inhibitor for NLRP3 inflammasome activation. INF39 specifically suppresses NLRP3 activation but not the NLRC4 or AIM2 inflammasomes. INF39 has no effect on K efflux, ROS generation or mitochondrial membrane potential, which are the upstream events of NLRP3 inflammasome activation. In addition, INF39 has no direct inhibitory effect on GSDMD, which is the downstream event of inflammasomes. More importantly, INF39 inhibits the interaction of NEK7-NLRP3, and subsequently inhibits interaction of NLRP3-NLRP3, NLRP3-ASC, ASC oligomerization and speckle formation. Altogether, our study unveils a deeper anti-inflammatory mechanism for INF39 and suggests it could serve as a lead for developing novel therapeutics combating NLRP3-driven diseases.
INF39 是一种无毒、不可逆的丙烯酰基 NLRP3 抑制剂，是乙基 2-((2-氯苯基)羟基)甲基)丙烯酸酯（INF4E）的进一步优化。然而，其抗炎活性的详细机制和直接靶标尚不清楚。在这里，我们表明 INF39 是 NLRP3 炎症小体激活的特异性抑制剂。INF39 特异性抑制 NLRP3 激活，但不抑制 NLRC4 或 AIM2 炎症小体。INF39 对 K+外流、ROS 生成或线粒体膜电位没有影响，这些都是 NLRP3 炎症小体激活的上游事件。此外，INF39 对 GSDMD 没有直接的抑制作用，GSDMD 是炎症小体的下游事件。更重要的是，INF39 抑制 NEK7-NLRP3 的相互作用，进而抑制 NLRP3-NLRP3、NLRP3-ASC、ASC 寡聚化和斑点形成的相互作用。总之，我们的研究揭示了 INF39 更深层次的抗炎机制，并表明它可以作为开发针对 NLRP3 驱动疾病的新型治疗方法的先导。
