NOD-like Receptors in Intestinal Inflammation

摘要 天然免疫受体的发现使天然免疫领域发生了革命性的变化。意想不到的 研究发现，先天免疫受体不仅位于细胞膜上，而且大多数是 在细胞内发现的。这使得细胞能够检测到病原体相关分子的细胞内扰动 模式(PAMP)或来自与损伤相关的分子模式(DAMPS)。我们的研究揭示了 细胞内天然免疫受体在抗炎和塑造微生物群中的新作用 在炎症性肠病(IBD)期间。中心假设是抑制的双向相互作用 微生物体内的细胞内天然受体是IBD的主要致病因素。我们的建议侧重于 细胞内的NLR(核苷酸结合区，富含亮氨酸重复序列的蛋白，或Nod样受体) 蛋白质。虽然NOD2在克罗恩氏病中仍然是最突出的，但我们已经关注了其他 结肠炎中的NLRs。我们有数据表明，几种抑制性NLR蛋白可以强烈缓解肠道症状 通过减少免疫信号通路的激活从而阻止炎性细胞因子的炎症 这是结肠炎不可或缺的反应。这反过来会影响先天免疫细胞和获得性免疫细胞，以及 结肠上皮细胞。我们还表明，这些抑制性NLR影响微生物群，部分是通过 维持能够包含促炎反应的细菌。因此，第一个目标是理解 抑制性NLR与肠道微生物区系双向相互作用减轻小鼠肠道炎症 使用项目2、4和动物模型核心A。另一个总体目标是评估 在小鼠身上获得的结果与人类的翻译相关性。处理项目3和人体组织 和基因组学核心B，我们将分析患者来源的材料，以验证我们的发现在小鼠身上的意义 炎症性肠病患者样本。

ABSTRACT The discovery of innate immune receptors has revolutionized the field of innate immunity. An unexpected finding is that innate immune receptor are not only located on the cell membrane, but a majority of these are found intracellularly. This allows cells to detect intracellular perturbation from pathogen-associated molecular patterns (PAMPs) or from damage-associated molecular patterns (DAMPs). Our studies have revealed a novel roles of intracellular innate immune receptor in attenuating inflammation and shaping the microbiome during inflammatory bowel disease (IBD). The central hypothesis is that the bi-directional interplay of inhibitory intracellular innate receptors with the microbiome is a major contributing factor in IBD. Our proposal focuses on the intracellular NLR (nucleotide-binding domain, leucine-rich repeat containing protein, or NOD-like receptor) proteins. While NOD2 remains the most prominent in Crohns’ disease, we have focused on the role of other NLRs in colitis. We have data to show that several inhibitory NLR proteins strongly mitigate intestinal inflammation by reducing the activation of immune signaling pathway thus preventing an inflammatory cytokine response that is integral to colitis. This in turn can affect both innate and adaptive immune cells, as well as colon epithelial cells. We have also shown that these inhibitory NLRs affect the microbiome, partly by maintaining bacteria that can contain a pro-inflammatory response. Thus the first goal is to understand the bidirectional interaction of inhibitory NLR and the gut microbiota in mitigating gut inflammation in mice by working with Projects 2, 4 and the Animal Models Core A. Another over-arching goal is to assess the translational relevance of results obtained in mice to humans. Working with Project 3 and the Human Tissue and Genomics Core B, we will analyze patient-derived material to verify the significance of our findings in mice to inflammatory bowel disease patient samples.