TY - JOUR T1 - NLRP3炎症小体途径在结节病中被激活并参与肉芽肿形成JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00119-2019 SP - 1900119 AU - Huppertz, Christine AU - Jäger, Benedikt AU - Wieczorek, Grazyna AU - Engelhard, Peggy AU - Oliver, Stephen J. AU - Bauernfeind, Franz-Georg AU - Littlewood-Evans, Amanda AU - Welte, Tobias AU - Hornung, Veit AU - Prasse，Antje Y1 - 20/01/01 UR - //www.qdcxjkg.com/content/early/2020/01/03/13993003.00119-2019.abstract N2 -结节病是一种以肉芽肿形成为特征的疾病。除了皮质类固醇之外，对新的治疗策略的需求还没有得到满足。NLRP3炎性小体途径在先天免疫细胞中表达，可感知危险信号以诱导炎性IL-1β，最近已成为一种可药物靶点。这促使我们测试NLRP3炎症小体和IL-1β通路在肉芽肿形成和结节病中的作用。19名结节病患者和19名健康志愿者(HV)被纳入这项初步研究。使用免疫组织化学、Western blot、RT-PCR和ELISA检测bal细胞、肺和皮肤活检中的NLRP3炎性小体活性。在体内实验中，我们使用海藻糖6,6二分枝酸盐(TDM)-肉芽肿小鼠模型，评估miR-223 KO和NLRP3 KO小鼠肺肉芽肿负担，以及MCC950和抗il -1β抗体治疗的治疗效果。我们发现NLRP3炎症小体通路强烈上调，激活的NLRP3炎症小体成分的表达，包括肺肉芽肿中裂解的caspase-1和IL-1β，与HV相比，结节患者bal细胞中IL-1β释放增加(p=0.006)。在结节病患者的肺泡巨噬细胞中，下调NLRP3的微RNA miR-223 mRNA水平降低，NLRP3 mRNA相应升高(p<0.005)。与野生型相比，NLRP3 KO小鼠肉芽肿形成减少，miR-223 KO小鼠肉芽肿形成增加。 Pharmacological interference using NLRP3 pathway inhibitor MCC950 or an anti-IL-1β antibody resulted in reduced granuloma formation (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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Huppertz reports other from Novartis Pharma AG, during the conduct of the study; other from Novartis Pharma AG, outside the submitted work.Conflict of interest: Dr. Jäger has nothing to disclose.Conflict of interest: Dr. Wieczorek reports other from Novartis Pharma AG, during the conduct of the study; other from Novartis Pharma AG, outside the submitted work.Conflict of interest: Dr. Engelhard has nothing to disclose.Conflict of interest: Dr. Oliver reports other from Novartis Pharma AG, during the conduct of the study; other from Novartis Pharma AG, outside the submitted work.Conflict of interest: Dr. Bauernfeind has nothing to disclose.Conflict of interest: Dr. Littlewood-Evans reports other from Novartis Pharma AG, during the conduct of the study; other from Novartis Pharma AG, outside the submitted work.Conflict of interest: Dr. Welte reports grants from Novartis, during the conduct of the study; personal fees from Novartis, outside the submitted work.Conflict of interest: Dr. Hornung has nothing to disclose.Conflict of interest: 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. ER -