Department of General Practice, Qilu Hospital, Cheeloo college of medicine, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
Department of Critical Care Medicine, The First Affiliated Hospital of Shandong First Medical University＆Shandong Provincial Qianfoshan Hospital, Shandong medicine and Health Key Laboratory of Emergency Medicine, Shandong Institute of Anesthesia and Respiratory Critical Medicine.
Int Immunopharmacol. 2022 Mar;104:108513. doi: 10.1016/j.intimp.2021.108513. Epub 2022 Jan 8.
The NLRP3 inflammasome plays a vital role in inflammation by increasing the maturation of interleukin-1β (IL-1β) and promoting pyroptosis. Given that C1q/tumour necrosis factor-related protein-9 (CTRP9) has been shown to be involved in diverse inflammatory diseases, we sought to assess the underlying impact of CTRP9 on NLRP3 inflammasome activation. In vitro, macrophages isolated from murine peritonea were stimulated with exogenous CTRP9, followed by lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP). We demonstrated that CTRP9 markedly augmented the activation of the NLRP3 inflammasome, as shown by increased mature IL-1β secretion, triggering ASC speck formation and promoting pyroptosis. Mechanistically, CTRP9 increased the levels of NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). Suppressing ROS with N-acetylcysteine (NAC) or interfering with NOX2 by small interfering RNA weakened the promoting effect of CTRP9 on the NLRP3 inflammasome. Furthermore, NLRP3 inflammasome activation, pyroptosis and secretion of mature IL-1β were significantly decreased in macrophages from CTRP9-KO mice compared to those from WT mice with the same treatment. In vivo, we established a sepsis model by intraperitoneal injection of LPS into WT and CTRP9-KO mice. CTRP9 knockout improved the survival rates of the septic mice and attenuated NLRP3 inflammasome-mediated inflammation. In conclusion, our study indicates that CTRP9 aggravates LPS-induced inflammation by promoting NLRP3 inflammasome activation via the NOX2/ROS pathway. CTRP9 could be a promising target for NLRP3 inflammasome-driven inflammatory diseases.
NLRP3 炎性小体通过增加白细胞介素-1β（IL-1β）的成熟和促进细胞焦亡，在炎症中发挥重要作用。鉴于 C1q/肿瘤坏死因子相关蛋白-9（CTRP9）已被证明参与多种炎症性疾病，我们试图评估 CTRP9 对 NLRP3 炎性小体激活的潜在影响。在体外，用外源性 CTRP9 刺激从小鼠腹膜分离的巨噬细胞，然后用脂多糖（LPS）和三磷酸腺苷（ATP）刺激。我们证明 CTRP9 显著增强 NLRP3 炎性小体的激活，表现为成熟的 IL-1β 分泌增加，触发 ASC 斑点形成并促进细胞焦亡。在机制上，CTRP9 增加 NADPH 氧化酶 2（NOX2）衍生的活性氧（ROS）的水平。用 N-乙酰半胱氨酸（NAC）抑制 ROS 或用小干扰 RNA 干扰 NOX2 削弱了 CTRP9 对 NLRP3 炎性小体的促进作用。此外，与用相同处理的 WT 小鼠相比，CTRP9-KO 小鼠的巨噬细胞中 NLRP3 炎性小体激活、细胞焦亡和成熟的 IL-1β 分泌明显减少。在体内，我们通过向 WT 和 CTRP9-KO 小鼠腹腔内注射 LPS 建立脓毒症模型。CTRP9 敲除提高了脓毒症小鼠的存活率，并减轻了 NLRP3 炎性小体介导的炎症。总之，我们的研究表明，CTRP9 通过 NOX2/ROS 途径促进 NLRP3 炎性小体激活，加重 LPS 诱导的炎症。CTRP9 可能是 NLRP3 炎性小体驱动的炎症性疾病的一个有希望的靶点。
Int Immunopharmacol. 2019-11-11
Chin Med J (Engl). 2024-7-5
J Biol Chem. 2018-11-19
Front Immunol. 2018-4-10
Open Life Sci. 2025-7-11
Zotero 插件