Role of apoptosis in the intestinal epithelium during homeostasis and disease

提案摘要 肠上皮通过形成一个物理屏障来保护肠道免受食物抗原和肠道微生物群的侵害。 屏障，并积极分泌粘液和抗菌肽。肠上皮细胞由一种 通过细胞分裂、分化和凋亡的周期不断更新的过程。细胞凋亡是一 调节性CD4 T（Treg）细胞和免疫耐受的强效诱导剂。在感染过程中，细胞凋亡诱导细胞凋亡。 定制的CD4 T辅助细胞17（TH17）应答。肠上皮细胞（IEC）凋亡是否起作用 肠耐受性和效应器反应尚不清楚。专职单核吞噬细胞（MP），如 作为巨噬细胞和树突状细胞（DC），在感染期间清除微生物病原体， 胚胎发育和组织重塑。虽然许多注意力集中在MP抽样， 肠道内的细菌和病原微生物，对采样的关注较少 尽管细胞凋亡在肠上皮细胞中起着重要作用，干扰 IEC中细胞凋亡的自然循环导致小鼠模型中的肠道炎症。IEC增加 炎症性肠病（IBD）患者的死亡和肠上皮损伤， 肠道功能障碍和炎症。几项国际IBD全基因组关联研究（GWAS）和 荟萃分析将IBD的易感性与参与先天免疫调节途径的基因相关， 反应，免疫调节细胞因子和TH17信号传导。来自不同鼠细胞的基因表达数据 型已经显示出IBD基因在先天免疫细胞，特别是DC中的最强富集。占据 了解肠上皮细胞凋亡是否以及如何影响耐受过程 因此肠道内的免疫力至关重要。 使用两种新的小鼠模型，我们将确定如何增加或削弱细胞凋亡， 肠上皮影响肠内的稳态和免疫应答。我们有令人信服 有证据表明，小肠上皮细胞凋亡不是旁观者事件，而是主动印记板层 固有MP具有“抑制炎症”和“诱导Treg细胞”的转录特征。值得注意的是， 在凋亡IEC摄取后MP中差异调节的许多基因与IBD基因重叠。这里我们 将检查结肠MP在稳态和感染期间的身份和概况。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 和肠道中的效应器反应。这包括它们对微生物成分的反应， 先天性淋巴样细胞，以及它们对Treg和TH17细胞命运的指示。所有这些参数都被打乱， IBD。通过这些研究的完成，我们将对细胞凋亡在肠上皮细胞中的作用有新的认识， 免疫调节，推进我们对粘膜内如何维持稳态的理解， 炎症性疾病如IBD的新疗法的开发阶段。

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.