抽象的
Sarcoidosis is a disease characterised by granuloma formation. There is an unmet need for new treatment strategies beyond corticosteroids. The NLRP3 inflammasome pathway is expressed in innate immune cells and senses danger signals to elicit inflammatory IL-1β and recently has become a druggable target. This prompted us to test the role of the NLRP3 inflammasome and IL-1β pathway in granuloma formation and sarcoidosis.
Nineteen sarcoid patients and 19 healthy volunteers (HV) were recruited into this pilot study. NLRP3 inflammasome activity was measured in BAL-cells and lung and skin biopsies using immunohistochemistry, Western blot, RT-PCR and ELISA. Forin vivoexperiments we used the trehalose 6,6 dimycolate (TDM)- granuloma mouse model and evaluated lung granuloma burden in miR-223 KO and NLRP3 KO mice as well as the treatment effects of MCC950 and anti-IL-1β antibody therapy.
我们发现NLRP3炎性体途径的强烈上调,通过激活的NLRP3炎性体成分的表达来证明,包括肺肉芽肿中裂解的caspase-1和IL-1β,与HV相比,从肺部肉芽肿中裂解了Bal细胞的IL-1β释放增加(P= 0.006)。miRNA水平的miRNA水平(一种下调NLRP3的微RNA)降低,NLRP3 mRNA在结节型患者的肺泡巨噬细胞中相应增加(p <0.005)。与野生型相比,NLRP3 KO小鼠显示出降低,而miR-223 KO小鼠的肉芽肿形成增加。使用NLRP3途径抑制剂MCC950或抗IL-1β抗体的药理干扰导致肉芽肿的形成减少(P <0.02)。
In conclusion, our data provide evidence of upregulated inflammasome and IL-1β pathway activation in sarcoidosis and suggest both as valid therapeutic targets.
脚注
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利益冲突:Huppertz博士在研究期间报告了Novartis Pharma Ag的其他报告;其他来自诺华药房的AG,在提交的工作之外。
利益冲突:Jäger博士没有什么可披露的。
利益冲突:Wieczorek博士在研究期间报告了Novartis Pharma AG的其他报告;其他来自诺华药房的AG,在提交的工作之外。
冲突的兴趣st: Dr. Engelhard has nothing to disclose.
冲突的兴趣st: Dr. Oliver reports other from Novartis Pharma AG, during the conduct of the study; other from Novartis Pharma AG, outside the submitted work.
利益冲突:Bauernfeind博士没有什么可披露的。
冲突的兴趣st: Dr. Littlewood-Evans reports other from Novartis Pharma AG, during the conduct of the study; other from Novartis Pharma AG, outside the submitted work.
冲突的兴趣st: Dr. Welte reports grants from Novartis, during the conduct of the study; personal fees from Novartis, outside the submitted work.
冲突的兴趣st: Dr. Hornung has nothing to disclose.
冲突的兴趣st: Dr. Prasse reports grants from Novartis Research Grant, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, personal fees from Roche, personal fees from Novartis, personal fees from Sanofi Aventis, grants and personal fees from Astra Zeneca, outside the submitted work.
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脚注
↵†两位作者都同样贡献
- 已收到January 17, 2019.
- Accepted2019年12月18日。
- 复制right ©ERS 2020