1 Merck Research Laboratories, Boston, MA, USA.
2 Diversigen, Inc. Houston, TX, USA.
Innate Immun. 2019 Feb;25(2):132-143. doi: 10.1177/1753425919826367.
Crohn's disease (CD) is a chronic disorder of the gastrointestinal tract characterized by inflammation and intestinal epithelial injury. Loss of function mutations in the intracellular bacterial sensor NOD2 are major risk factors for the development of CD. In the absence of robust bacterial recognition by NOD2 an inflammatory cascade is initiated through alternative PRRs leading to CD. In the present study, MCC950, a specific small molecule inhibitor of NLR pyrin domain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate (DSS)-induced intestinal inflammation in Nod2 mice. NLRP3 inflammasome formation was observed at a higher rate in NOD2-deficient small intestinal lamina propria cells after insult by DSS. NLRP3 complex formation led to an increase in IL-1β secretion in both the small intestine and colon of Nod2ko mice. This increase in IL-1β secretion in the intestine was attenuated by MCC950 leading to decreased disease severity in Nod2ko mice. Our work suggests that NLRP3 inflammasome activation may be a key driver of intestinal inflammation in the absence of functional NOD2. NLRP3 pathway inhibition can prevent intestinal inflammation in the absence of robust NOD2 signaling.
克罗恩病（CD）是一种慢性胃肠道疾病，其特征为炎症和肠道上皮损伤。细胞内细菌传感器 NOD2 的功能丧失突变是 CD 发展的主要危险因素。在 NOD2 无法识别细菌的情况下，通过替代 PRRs 引发炎症级联反应，导致 CD。在本研究中，NLR pyrin 结构域蛋白 3（NLRP3）的特异性小分子抑制剂 MCC950 可消除 Nod2 小鼠的葡聚糖硫酸钠（DSS）诱导的肠道炎症。在受到 DSS 刺激后，NOD2 缺陷的小肠固有层细胞中观察到 NLRP3 炎性小体形成的速度更快。NLRP3 复合物的形成导致 Nod2ko 小鼠的小肠和结肠中 IL-1β 的分泌增加。MCC950 可减弱这种 IL-1β 分泌的增加，从而减轻 Nod2ko 小鼠的疾病严重程度。我们的工作表明，在缺乏功能性 NOD2 的情况下，NLRP3 炎性小体的激活可能是肠道炎症的关键驱动因素。NLRP3 途径的抑制可以在缺乏强大的 NOD2 信号的情况下预防肠道炎症。
