Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome
Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome
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DOI：
10.1136/gut.2009.197822
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发表时间：
2010-09-01
期刊：
影响因子：
24.5
通讯作者：
Schnurr, Max
中科院分区：
文献类型：
--
作者：
Bauer, Christian;Duewell, Peter;Schnurr, Max
背景促炎细胞因子IL-1β和IL-18在炎症性肠病(IBD)的发病机制中发挥重要作用。对各种微生物成分和结晶物质的反应，这两种细胞因子都是通过caspase-1激活的多蛋白复合体NLRP3炎症体来处理的。方法以L-/-小鼠为模型，研究了NLRP3炎症体在葡聚糖硫酸钠诱导的实验性结肠炎中的作用。方法观察了野生型Caspase-1(-/-)、NLRP3(-/-)、ASC(-/-)、组织蛋白酶B-/-或组织蛋白酶B-/-小鼠巨噬细胞产生IL-1b的情况。用DSS灌胃诱导C57BL/6和NLRP3(-/-)小鼠结肠炎。每天评估一次临床疾病活动评分。结果体外培养的巨噬细胞与DSS孵育后，以caspase-1依赖的方式分泌高水平的IL-1b。缺乏NLRP3、ASC或caspase-1的巨噬细胞IL-1b的分泌被抑制，表明DSS通过NLRP3炎症小体激活caspase-1。此外，IL-1b的分泌依赖于吞噬功能、溶酶体成熟、组织蛋白酶B和L以及活性氧(ROS)。口服DSS后，NLRP3(-/-)小鼠的结肠炎程度低于野生型小鼠，结肠组织中的促炎细胞因子水平也较低。结论NLRP3炎症性小体是DSS结肠炎模型肠炎发生的重要机制之一。NLRP3炎性小体可能成为开发IBD新疗法的潜在靶点。
Background The proinflammatory cytokines interleukin 1 beta (IL-1 beta) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined.Methods IL-1b production in response to DSS was studied in macrophages of wild-type, caspase-1(-/-), NLRP3(-/-), ASC(-/-), cathepsin B-/- or cathepsin L-/- mice. Colitis was induced in C57BL/6 and NLRP3(-/-) mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue.Results Macrophages incubated with DSS in vitro secreted high levels of IL-1b in a caspase-1-dependent manner. IL-1b secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1b secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3(-/-) mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency.Conclusions The NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.