NEK7基因敲低可通过抑制NLRP3的激活来减轻ACLT诱导的小鼠膝关节骨关节炎。

IF 3.3 4区 医学 Q3 IMMUNOLOGY
Autoimmunity Pub Date : 2022-09-01 Epub Date: 2022-07-07 DOI:10.1080/08916934.2022.2093861
Wei Sun, Maoxing Yue, Guangmin Xi, Kai Wang, Jiaming Sai
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引用次数: 4

摘要

骨关节炎被认为是一种nlrp3相关疾病。NEK7是NLRP3炎性体激活的重要介质。本研究旨在证明NEK7是否在骨关节炎的发病机制中具有调节作用。采用前交叉韧带横断性骨关节炎(ACLT)方法建立C57BL/6小鼠骨关节炎动物模型。将表达NEK7特异性shRNA的腺相关病毒(adeno-associated virus, AAV)注入小鼠膝关节,通过免疫组化、qRT-PCR、western blotting、Safranin-O Fast Green染色、ELISA和免疫共沉淀法检测NEK7的作用。NEK7在ACLT小鼠关节组织中高表达。与shScr相比,AAV递送NEK7 shRNA可显著抑制软骨退变、OARSI评分和血清CTX-II和COMP水平。AAV递送NEK7 shRNA下调基质降解酶(ADAMTS-4、MMP3和MMP13)的表达,上调ecm相关分子(SOX9、collagen II和aggrecan)的表达。此外,AAV递送NEK7 shRNA可减轻aclt诱导的滑膜炎症,其证据是TNF-α、IL-6、IL-1β和IL-18水平降低,IL-10水平升高。在ACLT小鼠关节组织中,NEK7与NLRP3蛋白相互作用。AAV递送NEK7 shRNA抑制蛋白相互作用,从而抑制NLRP3炎性体的激活。AAV递送NEK7 shRNA对Nlrp3-/-小鼠的软骨退变和滑膜炎症无显著影响。综上所述,NEK7的下调可能通过抑制NLRP3炎性体的激活而发挥抗骨关节炎的作用。本研究提供了NEK7-NLRP3相互作用影响骨关节炎的新机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Knockdown of NEK7 alleviates anterior cruciate ligament transection osteoarthritis (ACLT)-induced knee osteoarthritis in mice via inhibiting NLRP3 activation.

Osteoarthritis is thought to be a NLRP3-related disease. NEK7 is an essential mediator for NLRP3 inflammasome activation. This study aimed to demonstrate whether NEK7 has regulatory roles in the pathogenesis of osteoarthritis. C57BL/6 mice were subjected to anterior cruciate ligament transection osteoarthritis (ACLT) for constructing animal models of osteoarthritis. Injection of adeno-associated virus (AAV) expressing NEK7-specific shRNA into the knee joints of mice, following of which immunohistochemistry, qRT-PCR, western blotting, Safranin-O Fast Green staining, ELISA, and co-immunoprecipitation were performed to determine the effects of NEK7. NEK7 was highly expressed in the joint tissues of ACLT mice. As compared with shScr, AAV delivery of NEK7 shRNA significantly inhibited cartilage degeneration, OARSI score, and serum CTX-II and COMP levels. AAV delivery of NEK7 shRNA downregulated the expression of matrix-degrading enzymes (ADAMTS-4, MMP3, and MMP13) and upregulated the expression of ECM-related molecules (SOX9, collagen II, and aggrecan). In addition, AAV delivery of NEK7 shRNA alleviated ACLT-induced synovial inflammation, as was evidenced by the decreased levels of TNF-α, IL-6, IL-1β, and IL-18 and increased levels of IL-10. In the joint tissues of ACLT mice, NEK7 interacted with NLRP3 proteins. AAV delivery of NEK7 shRNA inhibited the protein interaction, and thereby inhibited the activation of the NLRP3 inflammasome. AAV delivery of NEK7 shRNA has no significant effects on cartilage degeneration and synovial inflammation in Nlrp3-/- mice. In conclusion, knockdown of NEK7 exerted anti-osteoarthritic effects, possibly via inhibiting the activation of the NLRP3 inflammasome. This study provided a novel mechanism of NEK7-NLRP3 interaction affecting osteoarthritis.

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来源期刊
Autoimmunity
Autoimmunity 医学-免疫学
CiteScore
5.70
自引率
8.60%
发文量
59
审稿时长
6-12 weeks
期刊介绍: Autoimmunity is an international, peer reviewed journal that publishes articles on cell and molecular immunology, immunogenetics, molecular biology and autoimmunity. Current understanding of immunity and autoimmunity is being furthered by the progress in new molecular sciences that has recently been little short of spectacular. In addition to the basic elements and mechanisms of the immune system, Autoimmunity is interested in the cellular and molecular processes associated with systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, type I diabetes, multiple sclerosis and other systemic and organ-specific autoimmune disorders. The journal reflects the immunology areas where scientific progress is most rapid. It is a valuable tool to basic and translational researchers in cell biology, genetics and molecular biology of immunity and autoimmunity.
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