Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, 230 Filley Hall, Lincoln, NE 68583-0922, USA.
Center for Biotechnology, University of Nebraska-Lincoln, E117 Beadle Center, Lincoln, NE 68588-0665, USA.
Theranostics. 2021 Sep 7;11(19):9311-9330. doi: 10.7150/thno.60265. eCollection 2021.
Aberrant activation of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome drives the development of many complex inflammatory diseases, such as obesity, Alzheimer's disease, and atherosclerosis. However, no medications specifically targeting the NLRP3 inflammasome have become clinically available. Therefore, we aim to identify new inhibitors of the NLRP3 inflammasome in this study. Vesicle-like nanoparticles (VLNs) were extracted from garlic chives and other vegetables and their effects on the NLRP3 inflammasome were evaluated in primary macrophages. After garlic chive-derived VLNs (GC-VLNs) were found to exhibit potent anti-NLRP3 inflammasome activity in cell culture, such function was further assessed in a murine acute liver injury disease model, as well as in diet-induced obesity. Finally, GC-VLNs were subjected to omics analysis to identify the active components with anti-NLRP3 inflammasome function. GC-VLNs are membrane-enclosed nanoparticles containing lipids, proteins, and RNAs. They dose-dependently inhibit pathways downstream of NLRP3 inflammasome activation, including caspase-1 autocleavage, cytokine release, and pyroptotic cell death in primary macrophages. The inhibitory effects of GC-VLNs on the NLRP3 inflammasome are specific, considering their marginal impact on activation of other inflammasomes. Local administration of GC-VLNs in mice alleviates NLRP3 inflammasome-mediated inflammation in chemical-induced acute liver injury. When administered orally or intravenously, GC-VLNs accumulate in specific tissues and suppress activation of the NLRP3 inflammasome and chronic inflammation in diet-induced obese mice. The phospholipid 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) in GC-VLNs has been identified to inhibit NLRP3 inflammasome activation. Identification of GC-VLNs and their active component DLPC as potent inflammasome inhibitors provides new therapeutic candidates in the treatment of NLRP3 inflammasome-driven diseases.
核苷酸结合域和富含亮氨酸重复序列相关（NLR）家族的异常激活，吡咯烷酮域包含 3（NLRP3）炎性小体驱动许多复杂炎症性疾病的发展，如肥胖、阿尔茨海默病和动脉粥样硬化。然而，没有专门针对 NLRP3 炎性小体的药物在临床上可用。因此，我们旨在本研究中鉴定 NLRP3 炎性小体的新抑制剂。
从葱和其他蔬菜中提取囊泡样纳米颗粒（VLN），并在原代巨噬细胞中评估其对 NLRP3 炎性小体的作用。发现葱衍生的 VLN（GC-VLN）在细胞培养中具有强大的抗 NLRP3 炎性小体活性后，进一步在小鼠急性肝损伤疾病模型以及饮食诱导的肥胖中评估其功能。最后，对 GC-VLN 进行组学分析以鉴定具有抗 NLRP3 炎性小体功能的活性成分。
GC-VLN 是含有脂质、蛋白质和 RNA 的膜封闭纳米颗粒。它们剂量依赖性地抑制 NLRP3 炎性小体激活下游的途径，包括半胱天冬酶-1 自身切割、细胞因子释放和原代巨噬细胞中的细胞焦亡。考虑到 GC-VLN 对其他炎性小体激活的影响微不足道，GC-VLN 对 NLRP3 炎性小体的抑制作用是特异性的。GC-VLN 在小鼠中的局部给药可减轻化学诱导的急性肝损伤中 NLRP3 炎性小体介导的炎症。口服或静脉内给予 GC-VLN 时，它们会在特定组织中积累并抑制饮食诱导肥胖小鼠中 NLRP3 炎性小体和慢性炎症的激活。GC-VLN 中的磷脂 1,2-二亚油酰基-sn-甘油-3-磷酸胆碱（DLPC）已被鉴定为抑制 NLRP3 炎性小体激活。
鉴定 GC-VLN 及其活性成分 DLPC 作为有效的炎性小体抑制剂为 NLRP3 炎性小体驱动的疾病的治疗提供了新的治疗候选物。
