RICK/RIP2 is a NOD2-independent nodal point of gut inflammation
RICK/RIP2 is a NOD2-independent nodal point of gut inflammation
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DOI：
10.1093/intimm/dxz045
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发表时间：
2019-10-01
影响因子：
4.4
通讯作者：
Strober, Warren
中科院分区：
文献类型：
--
作者：
Watanabe, Tomohiro;Minaga, Kosuke;Strober, Warren
先前的研究已经表明，抑制受体相互作用丝氨酸/苏氨酸激酶（RICK）（也称为RIP 2）导致实验性结肠炎的改善。这种作用主要归因于核苷酸结合寡聚化结构域2（NOD 2）信号传导，因为后者被认为是RICK活化的主要诱导物。在这项研究中，我们探讨了RICK介导的炎症性肠病（IBD）抑制的分子机制。在最初的一系列研究集中在三硝基苯磺酸（TNBS）-结肠炎和葡聚糖硫酸钠（DSS）-结肠炎，我们表明，下调肠道RICK表达的NOD 2-完整的小鼠直肠内给药的质粒表达RICK特异性siRNA伴随着下调促炎细胞因子反应在结肠和保护小鼠免受实验性结肠炎。有些令人惊讶的是，直肠内施用RICK-siRNA还抑制NOD 2缺陷小鼠和NOD 1/NOD 2双缺陷小鼠中的TNBS-结肠炎和DSS-结肠炎。在对患有IBD的人的补充研究中，我们发现，与没有NOD 1或NOD 2表达显著升高的对照相比，RICK、细胞凋亡抑制蛋白2（cIAP 2）和下游信号传导伙伴的表达在IBD的炎症组织中显著增加。此外，RICK表达的增加与疾病活动和促炎细胞因子反应相关。因此，这些研究表明，NOD 1-或NOD 2-独立的RICK激活在小鼠实验性结肠炎和人IBD中起主要作用。
Previous studies have shown that inhibition of receptor-interacting serine/threonine kinase (RICK) (also known as RIP2) results in amelioration of experimental colitis. This role has largely been attributed to nucleotide-binding oligomerization domain 2 (NOD2) signaling since the latter is considered a major inducer of RICK activation. In this study, we explored the molecular mechanisms accounting for RICK-mediated inhibition of inflammatory bowel disease (IBD). In an initial series of studies focused on trinitrobenzene sulfonic acid (TNBS)-colitis and dextran sodium sulfate (DSS)-colitis we showed that down-regulation of intestinal RICK expression in NOD2-intact mice by intra-rectal administration of a plasmid expressing RICK-specific siRNA was accompanied by down-regulation of pro-inflammatory cytokine responses in the colon and protection of the mice from experimental colitis. Somewhat surprisingly, intra-rectal administration of RICK-siRNA also inhibited TNBS-colitis and DSS-colitis in NOD2-deficient and in NOD1/NOD2-ouble deficient mice. In complementary studies of humans with IBD we found that expression of RICK, cellular inhibitor of apoptosis protein 2 (cIAP2) and downstream signaling partners were markedly increased in inflamed tissue of IBD compared to controls without marked elevations of NOD1 or NOD2 expression. In addition, the increase in RICK expression correlated with disease activity and pro-inflammatory cytokine responses. These studies thus suggest that NOD1- or NOD2-independenent activation of RICK plays a major role in both murine experimental colitis and human IBD.