Pathophysiology of TLR5KO Colitis

描述（由申请人提供）：炎症性肠病（IBD）与对肠道菌群的香柏子粘膜免疫反应有关。先天免疫驱动疾病的活跃耀斑，而适应性免疫反应被认为维持慢性炎症状态。虽然IBD通常与对肠道细菌的免疫反应升高有关，但最近IBD患者先天免疫水平受损的研究结果表明，事实上，至少一些IBD的发病率实际上可能是由潜在的先天免疫缺陷引起的。因此，从机制上剖析先天免疫的改变如何最终导致慢性炎症，应该有助于理解IBD的病理生理学。细菌蛋白鞭毛蛋白是鞭毛的单体亚基，是肠上皮细胞的显性先天免疫激活剂。因此，鞭毛蛋白受体toll样受体5 （TLR5）的实验研究可能为先天免疫改变如何导致IBD提供机制见解。因此，我们最近观察到TLR5-KO小鼠发生自发性结肠炎。这种结肠炎与肠道菌群的改变有关，似乎依赖于先天免疫和适应性免疫。因此，我们假设TLR5在“管理”共生菌群中起着至关重要的作用，TLR5的缺失使小鼠无法正确管理其共生菌群，从而导致其他先天免疫信号通路的慢性激活和“结肠炎”t细胞的发育。因此，我们建议：1)确定TLR5缺失如何影响免疫细胞，并研究其在TLR5KO结肠炎中的作用；2)确定TLR5缺失如何影响肠道微生物群，以及这种变化在结肠炎中的作用。

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) are associated with berrant mucosal immune responses to the enteric microflora. Innate immunity drives the active flares of disease while adaptive immune responses are thought to maintain the chronically inflamed state. While IBD has generally been associated with elevated immune responses to gut bacteria, the recent findings that IBD patients have impaired levels of innate immunity suggest that, in fact, at least some incidence of IBD may in fact result from an underlying innate immune deficiency. Thus, mechanistically dissecting how alterations in innate immunity can eventuate in chronic inflammation should help understand the pathophysiology of IBD. The bacterial protein flagellin, the monomeric subunit of flagella, is a dominant innate immune activator of intestinal epithelial cells. Thus, experimental study of the flagellin receptor, toll-like receptor 5 (TLR5), may provide mechanistic insights into how alterations in innate immunity can result in IBD. In accordance, we have recently observed that TLR5-KO mice develop spontaneous colitis. Such colitis is associated with alterations in gut microflora and appears to be dependent upon both innate and adaptive immunity. Thus, we hypothesize that TLR5 plays an essential role in "managing" the commensal microflora and that loss of TLR5 renders mice unable to properly manage their commensal microflora, resulting in chronic activation of other innate immune signaling pathways and development of "colitogenic" T-cells. Thus we propose to 1) Determine how loss of TLR5 affects immune cells and examine their role in TLR5KO colitis and 2) Define how loss of TLR5 affects the enteric microbiota and the role such changes play in driving colitis.