Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Respiratory Medicine, Second Affiliated Hospital of Hainan Medical University, Haikou, China.
Int Immunopharmacol. 2023 May;118:110024. doi: 10.1016/j.intimp.2023.110024. Epub 2023 Mar 21.
Aberrant activation of the NLRP3 inflammasome has been implicated in the occurrence and development of many inflammatory diseases, and thus potent inhibitors of the NLRP3 inflammasome should be explored. An antitumor agent, Leukadherin-1 (LA-1), tested in phase 1/2 clinical trials, has been reported to exert anti-inflammatory properties by blocking the NF-κB pathway. However, the effects of LA-1 on the NLRP3 inflammasome have not been conclusively determined. In this study, we found that at lower doses (below 1 μM) ex vivo, LA-1 blocked NLRP3 inflammasome activation without affecting NF-κB signaling. Accordingly, 1 mg/Kg LA-1 strongly inhibited the release of NLRP3-dependent cytokine, but only slightly inhibited NLRP3-independent-cytokines secretion in endotoxemia and alleviated NLRP3-dependent peritonitis in vivo. Mechanistically, LA-1 had no effects on ion flux or mitochondrial injury. Instead, it inhibited NLRP3 inflammasome assembly by suppressing ASC oligomerization, blocking NLRP3 self-assembly, and reducing interactions of NLRP3 with ASC and NEK7. Therefore, LA-1 inhibits NLRP3 inflammasome activation, implying that it is a potential treatment option for NLRP3-associated diseases.
NLRP3 炎性小体的异常激活与许多炎症性疾病的发生和发展有关，因此应该探索有效的 NLRP3 炎性小体抑制剂。一种抗肿瘤药物 Leukadherin-1（LA-1）已在 1/2 期临床试验中进行了测试，据报道，它通过阻断 NF-κB 通路发挥抗炎作用。然而，LA-1 对 NLRP3 炎性小体的影响尚未得到明确证实。在本研究中，我们发现，在较低剂量（低于 1 μM）下，LA-1 可在体外阻断 NLRP3 炎性小体的激活，而不影响 NF-κB 信号通路。因此，1mg/Kg 的 LA-1 可强烈抑制 NLRP3 依赖性细胞因子的释放，但仅轻度抑制内毒素血症中 NLRP3 非依赖性细胞因子的分泌，并减轻体内 NLRP3 依赖性腹膜炎。在机制上，LA-1 对离子流或线粒体损伤没有影响。相反，它通过抑制 ASC 寡聚化、阻断 NLRP3 自组装以及减少 NLRP3 与 ASC 和 NEK7 的相互作用来抑制 NLRP3 炎性小体的组装。因此，LA-1 抑制 NLRP3 炎性小体的激活，这意味着它是 NLRP3 相关疾病的潜在治疗选择。
