Pathophysiology of TLR5KO Colitis

描述(由申请人提供)：炎症性肠病(IBD)与对肠道微生物区系的强烈粘膜免疫反应有关。先天免疫驱动疾病的活跃爆发，而获得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增强有关，但最近的发现表明，IBD患者的先天免疫水平受损，事实上，至少部分IBD的发病率可能实际上是潜在的先天免疫缺陷造成的。因此，机械地剖析先天性免疫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。鞭毛蛋白是鞭毛的单体亚基，是肠道上皮细胞的主要天然免疫激活剂。因此，对鞭毛蛋白受体Toll样受体5(TLR5)的实验研究可能为先天性免疫改变如何导致IBD提供机制上的见解。因此，我们最近观察到TLR5-KO小鼠发生自发性结肠炎。这种结肠炎与肠道微生物区系的改变有关，似乎与先天免疫和获得性免疫有关。因此，我们假设TLR5在“管理”共生微生物区系中起着至关重要的作用，TLR5的缺失使小鼠不能正确地管理它们的共生微生物区系，导致其他先天免疫信号通路的慢性激活和“结肠性”T细胞的发展。因此，我们建议1)确定TLR5的缺失如何影响免疫细胞，并研究它们在TLR5KO结肠炎中的作用；2)确定TLR5的缺失如何影响肠道微生物区系，以及这些变化在推动结肠炎中的作用。 公共卫生相关性：在小鼠中，Toll样受体5(TLR5)的工程化缺失会导致桥脑结肠炎。这个项目试图确定这种结肠炎的病理生理机制。我们希望这些信息将被证明是对理解克罗恩病和溃疡性结肠炎的发病机制的有洞察力的，这些疾病统称为炎症性肠病。

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. PUBLIC HEALTH RELEVANCE: Engineered deletion toll-like receptor 5 (TLR5), in mice, results in pontaneous colitis. This project seeks to define the pathophysiologic mechanisms that underlie such colitis. We expect this information will prove insightful toward understanding the pathogenesis of Crohn's disease and ulcerative colitis, collectively referred to as inflammatory bowel disease.