Department of Nutrition and Health Sciences , University of Nebraska Lincoln , 230 Filley Hall , Lincoln , Nebraska 68583-0922 , United States.
Center for Biotechnology , University of Nebraska Lincoln , E117 Beadle Center, Lincoln , Nebraska 68588-0665 , United States.
Mol Pharm. 2019 Jun 3;16(6):2690-2699. doi: 10.1021/acs.molpharmaceut.9b00246. Epub 2019 Apr 30.
The nucleotide-binding domain and leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome is a key regulator of innate immune responses, and its aberrant activation is implicated in the pathogenesis of many diseases such as Alzheimer's disease and type 2 diabetes. Targeting the NLRP3 inflammasome could hold promise to combat these complex diseases, but therapies specifically inhibiting the NLRP3 inflammasome have not been developed for patient treatment. The current study aimed to identify food-borne exosome-like nanoparticles (ELNs) that inhibit NLRP3 inflammasome activity. Nine vegetables or fruits were selected to extract ELNs, which were examined for their inhibitory effects on activation of the NLRP3 inflammasome in primary macrophages. Although most of the tested ELNs posed minimal impacts, the ELNs from ginger rhizomes (G-ELNs) strongly inhibited NLRP3 inflammasome activation. The G-ELNs contained lipids, proteins, and RNAs and were easily taken up by macrophages. G-ELN treatment suppressed pathways downstream of inflammasome activation including caspase1 autocleavage, interleukin (IL)-1β and IL-18 secretion, and pyroptotic cell death. Apoptotic speck protein containing a caspase recruitment domain (ASC) oligomerization and speck formation assays indicated that G-ELNs blocked assembly of the NLRP3 inflammasome. The lipids in G-ELNs, rather than the RNAs or proteins, were responsible for the inhibitory activity observed. Together, the data suggested G-ELNs as new potent agents that block NLRP3 inflammasome assembly and activation. The unique features of G-ELNs including biomolecule protection and tissue bioavailability should facilitate the development of G-ELN-based therapy to target the NLRP3 inflammasome in the disease settings.
核苷酸结合域和富含亮氨酸重复序列家族，包含pyrin 结构域的 3（NLRP3）炎性小体是先天免疫反应的关键调节剂，其异常激活与阿尔茨海默病和 2 型糖尿病等许多疾病的发病机制有关。靶向 NLRP3 炎性小体可能有望治疗这些复杂疾病，但尚未开发出专门针对 NLRP3 炎性小体的治疗方法。本研究旨在鉴定抑制 NLRP3 炎性小体活性的食源性外体样纳米颗粒（ELNs）。选择 9 种蔬菜或水果提取 ELNs，检测其对原代巨噬细胞中 NLRP3 炎性小体激活的抑制作用。尽管大多数测试的 ELNs 影响较小，但姜根茎的 ELNs（G-ELNs）强烈抑制 NLRP3 炎性小体的激活。G-ELNs 含有脂质、蛋白质和 RNA，容易被巨噬细胞摄取。G-ELN 处理抑制了炎性小体激活的下游途径，包括半胱天冬酶 1 自身切割、白细胞介素（IL）-1β 和 IL-18 的分泌以及细胞焦亡。含有半胱天冬酶募集结构域（ASC）寡聚化和斑点形成测定的凋亡斑点蛋白表明，G-ELNs 阻断了 NLRP3 炎性小体的组装。G-ELNs 中的脂质而不是 RNA 或蛋白质负责观察到的抑制活性。总之，数据表明 G-ELNs 是新的有效药物，可阻断 NLRP3 炎性小体的组装和激活。G-ELNs 的独特特征，包括生物分子保护和组织生物利用度，应该有助于基于 G-ELN 的治疗方法的开发，以针对疾病环境中的 NLRP3 炎性小体。
