Role of apoptosis in the intestinal epithelium during homeostasis and disease

建议书摘要 肠道上皮对食物抗原和肠道微生物群的保护作用是通过形成物理的 阻隔并主动分泌粘液和抗微生物多肽。肠上皮由一种 通过细胞分裂、分化和凋亡的循环而不断更新的过程。细胞凋亡是一种 调节性CD4T(Treg)细胞和免疫耐受的有效诱导剂。在感染期间，细胞凋亡诱导一种 量身定制的CD4T辅助17(TH17)反应。肠上皮细胞(IEC)的凋亡是否起作用 在肠道耐受性和效应性尚不清楚。专业单核吞噬细胞(MP)，如 作为巨噬细胞和树突状细胞(DC)，感染期间的明确微生物病原体和感染期间的凋亡细胞 胚胎发育和组织重塑。虽然很多注意力都集中在MP抽样上 肠腔内的共生和致病微生物，较少关注采样 尽管细胞凋亡在肠道上皮细胞中起着重要作用，但对凋亡的IEC仍有影响。干扰 在小鼠模型中，IEC细胞凋亡的自然循环导致肠道炎症。增加了IEC 炎症性肠病(IBD)患者的死亡和肠道上皮损伤，这加剧了 肠易激障碍和炎症。几项国际IBD全基因组关联研究(GWAS)和 Meta分析表明IBD的易感性与调节先天免疫的基因有关 反应，免疫调节细胞因子，和TH17信号。不同小鼠细胞的基因表达数据 各种类型的IBD基因在先天性免疫细胞中表现出最强的丰富性，尤其是DC。获得了一个 了解肠上皮细胞凋亡是否及如何影响耐受过程 因此，肠道内的免疫力是至关重要的。 使用两个新的小鼠模型，我们将确定增加或损害细胞凋亡是如何 肠道上皮影响肠道内的动态平衡和免疫反应。我们有令人信服的 有证据表明，小肠上皮细胞的凋亡不是旁观者事件，而是主动印记板层 具有“抑制炎症”和“诱导Treg细胞”转录特征的专有MP。值得注意的是， 在MP中，许多在凋亡后IEC摄取后差异调节的基因与IBD基因重叠。在这里我们 将检查稳定状态和感染期间的结肠MP的身份和特征。我们将调查如何 细胞凋亡影响肠道MP的功能，因为它们与免疫耐受的各种机制有关 以及肠道中的效应器反应。这包括它们对微生物成分的反应、它们的维护 先天淋巴样细胞，以及它们对Treg和TH17细胞命运的指示。所有这些参数都在 IBD。随着这些研究的完成，我们将对细胞凋亡在肠道中的作用有了新的认识 免疫调节，促进我们对粘膜内如何维持动态平衡的理解，并设置 炎症性疾病如炎症性疾病的新疗法的发展阶段。

PROPOSAL SUMMARY The intestinal epithelium protects against food antigens and the luminal microbiota by forming a physical barrier and actively secreting mucous and anti-microbial peptides. The intestinal epithelium is maintained by a process of constant renewal through a cycle of cell division, differentiation, and apoptosis. Apoptosis is a potent inducer of regulatory CD4 T (TREG) cells and immune tolerance. During infection, apoptosis induces a tailored CD4 T helper 17 (TH17) response. Whether apoptosis of intestinal epithelial cells (IEC) plays any role in intestinal tolerance and effector response is not known. Professional mononuclear phagocytes (MP), such as macrophages and dendritic cells (DC), clear microbial pathogens during infection and apoptotic cells during embryonic development and tissue remodeling. While much attention has centered on MP sampling of commensal and pathogenic microorganisms within the gut lumen, less attention is directed towards sampling of apoptotic IEC, despite the prominent role that apoptosis plays in the intestinal epithelium. Interference with the natural cycle of apoptosis in IEC leads to intestinal inflammation in mouse models. There is increased IEC death and damage to the intestinal epithelium in patients with inflammatory bowel disease (IBD), and this fuels intestinal dybsiosis and inflammation. Several international IBD genome wide association studies (GWAS) and meta-analyses have associated susceptibility to IBD with genes involved in pathways regulating innate immune responses, immunomodulatory cytokines, and TH17 signaling. Gene expression data from different murine cell types have shown the strongest enrichment of IBD genes in innate immune cells, particularly DC. Gaining an understanding of whether and how apoptosis of the intestinal epithelium impacts the processes of tolerance and immunity within the intestine is therefore of utmost importance. Using two novel mouse models, we will determine how increasing or impairing apoptosis of the intestinal epithelium impacts the homeostatic and immune responses within the intestine. We have compelling evidence that apoptosis in the small intestinal epithelium is not a bystander event, but actively imprints lamina propria MP with `suppression of inflammation' and `induction of TREG cell' transcriptional signatures. Notably, many of the genes differentially modulated in MP after apoptotic IEC uptake overlap with IBD genes. Here we will examine the identities and profiles of colonic MP during steady state and infection. We will investigate how apoptosis impacts the functions of intestinal MP as they relate to various mechanisms of immune tolerance and effector response in the intestine. This includes their response to microbial components, their maintenance of innate lymphoid cells, and their instruction of TREG and TH17 cell fates. All these parameters are disrupted in IBD. By the completion of these studies, we will have gained new insights into the role of apoptosis in intestinal immune regulation, advance our understanding of how homeostasis is maintained within the mucosa, and set the stage for development of novel therapeutics for inflammatory diseases such as IBD.