Endogenous TLR1 signals prevent uncontrolled innate immunity in the colon

 描述（由申请人提供）：肠是我们身体最大的免疫系统网络之一、100万亿个肠道细菌和各种特化真核细胞（例如上皮细胞、潘氏细胞和产生粘液的杯状细胞）的复杂器官。肠道中存在高抗原负荷，因为它是病原体的常见进入部位、食物蛋白质的吸收部位和大量肠道细菌。免疫反应的失调可导致疾病，如炎症性肠病（IBD）或结肠炎相关的癌症。为了防止异常的免疫应答，这些区室之间的通信和调节是必不可少的。微生物世界与我们肠道的人类细胞非常接近，这表明识别保守微生物基序的先天受体，如Toll样受体（TLR），可能在调节体内平衡和炎症中发挥重要作用。我们以前的工作已经确定TLR 1作为一个重要的调解人的肠道免疫在病原体感染。此外，我们还发现， TLR 1的单核苷酸多态性与小儿IBD相关，TLR 1可消除表面表达和信号传导。此外，这种突变影响疾病的严重程度和对免疫疗法的反应。有趣的是，我们发现缺乏TLR 1信号传导的幼稚小鼠在结肠固有层中产生促炎性先天细胞因子IL-23和IL-1 β水平升高。IL-23和IL-1 β对于TH 17细胞和第3组先天淋巴样细胞（ILC 3）的扩增和维持是重要的。我们已经发现，TH 17细胞的稳态水平是正常的，然而ILC 3在TLR 1缺陷小鼠的结肠中显著增加。重要的是，已经在IBD患者中鉴定了ILC，尽管其诱导、调节和作用仍然未知。拟议的研究将检查在结肠中缺乏内源性TLR 1信号传导的情况下IL-23和IL-1 β的调节，以及这如何影响ILC 3的发展。具体来说，我们将确定IL-1 β和IL-23是否是ILC 3稳态增加所必需和足够的，并确定这种增加所必需的细胞类型。我们还将确定结肠中TLR 1信号传导的缺失如何导致IL-23和IL-1 β的上调。最后，由于ILC在结肠中既有保护作用又有致病作用，我们将研究在缺乏TLR 1信号传导的情况下诱导的ILC如何影响肠道炎症反应。这些研究的结果将有助于了解特异性TLR 1信号如何调节结肠中的先天免疫。此外，由于我们已经在IBD儿科患者中鉴定了TLR 1信号传导的突变，因此更好地理解TLR 1对先天免疫的调节可能会导致开发个性化疗法或治疗以预防疾病或复发。

 DESCRIPTION (provided by applicant): The intestine is a complex organ home to one of our body's largest immune system networks, 100 trillion commensal bacteria, and a variety of specialized eukaryotic cells, such as epithelium, Paneth cells and mucus- producing goblet cells. A high antigenic burden in the intestine exists because it is a common entry site for pathogens, the site for absorption of food proteins and the high number of commensal bacteria. Dysregulation of the immune responses can lead to disease such as inflammatory bowel disease (IBD) or colitis-associated cancers. In order to prevent aberrant immune responses communication and regulation between these compartments is essential. The close proximity of the microbial world to the human cells of our intestine suggest that innate receptors, such as Toll-like Receptors (TLR), which recognize conserved microbial motifs, may play an essential role in regulating homeostasis and inflammation. Our previous work has identified TLR1 as a critical mediator of intestinal immunity during pathogenic infection. Further, we have found that a single nucleotide polymorphism in TLR1, which abrogates surface expression and signaling, is associated with pediatric IBD. Further this mutation impacts disease severity and response to immune-therapies. Intriguingly, we have found that naïve mice deficient for TLR1 signaling produce elevated levels of the pro-inflammatory innate cytokines IL-23 and IL-1ß in the colonic lamina propria. IL-23 and IL-1ß are important for the expansion and maintenance of TH17 cells and group 3 innate lymphoid cells (ILC3). We have found that homeostatic levels of TH17 cells are normal, however ILC3 are significantly increased in the colons of TLR1-deficient mice. Importantly ILC have been identified in patients with IBD, though their induction, regulation and role are still unknown. The proposed research will examine the regulation of IL-23 and IL-1ß in the absence of endogenous TLR1 signaling in the colon and how this impacts the development of ILC3. Specifically, we will determine whether IL-1ß and IL-23 are necessary and sufficient for the homeostatic increase in ILC3 and determine the cell types necessary for this increase. We will also determine how the absence of TLR1 signaling in the colon leads to up-regulated IL-23 and IL-1ß. Lastly, as ILC can have both protective and pathogenic roles in the colon, we will examine how ILC induced in the absence of TLR1 signaling impacts intestinal inflammatory responses. The results of these studies will contribute to the understanding how specific TLR1 signals regulate of innate immunity in the colon. Further, as we have identified a mutation in TLR1 signaling in pediatric patients with IBD, a greater understanding of the regulation of innate immunity by TLR1 may lead to the development of individualized therapies or treatments to prevent disease or relapses.