炎症性肠病中CCL5缺失导致肠道菌群紊乱引发Th17/Treg失衡的机制研究

Inflammatory bowel disease (IBD), a group of intestinal inflammatory diseases, is complicated and difficult to cure. Studies have shown that the pathogenesis of IBD is induced by the mutation of key genes which leads to imbalance of intestinal microbial communities and immune system. Recent studies found that CCL5 plays an important role in IBD, but the mechanism is still unclear. In our previous study, by using DSS-induced intestinal inflammation model of CCL5-dificiency mice we found that CCL5-deficiency upregulated the ratio of Th17 to Treg cells by changing the intestinal microbial communities. Furthermore, we have identified that non-immune cells-derived CCL5 contributes to the role of CCL5 in IBD via bone marrow-chimeric mice. Therefore, our study will utilize the DSS-induced intestinal inflammation model to explore the mechanism on how CCL5 induced the alteration of the intestinal microbial communities and figure out how CCL5 regulated intestinal microbial communities to increase the ratio of Th17 to Treg cells in inflammatory bowel disease. What’s more, our study will explore the protective effect of CCL5 on intestinal mucosa through nanoparticles carring CCL5 protein. Finally, we would demonstrate that CCL5 can regulate the balance of intestinal microbial communities to maintain the polarization of CD4+ T cells of protecting the intestinal mucosa in human IBD organoid, which provided a new target for the treatment of IBD.

炎症性肠病(IBD)是一组病因复杂且难以治愈的肠道非特异性炎性疾病，其主要发病原因是关键基因的改变导致肠道菌群失衡和免疫系统失调。近年研究发现，CCL5在肠道菌群和免疫系统中发挥着重要作用，但机制尚不清楚。课题组通过对CCL5基因敲除小鼠的肠道炎症模型研究发现，CCL5缺失改变肠道菌群组成并导致CD4+T细胞中Th17/Treg比例上调，促进了肠道炎症；同时，通过对骨髓嵌合的肠道炎症小鼠模型研究证实，发挥作用的CCL5蛋白主要来源于肠道非免疫细胞。本课题将在DSS诱导的肠道炎症小鼠模型上：①阐明CCL5缺失对肠道菌群失衡的调控作用及其机制；②揭示肠道菌群失衡是如何上调Th17/Treg比例；③运用纳米材料靶向运送CCL5，探索其对肠粘膜的保护作用。最后，在人肠道IBD类器官培养体系中，进一步验证CCL5可调控肠道菌群平衡以维持CD4+T细胞正常极化来保护肠道粘膜，为IBD的治疗提供新靶标。

溃疡性结肠炎（UC）是一种慢性胃肠道疾病，以肠道炎症和上皮损伤为特征。尽管UC的病因多种多样，但免疫系统失衡是参与UC进展的一个共同特征。研究发现，CCL5在UC的免疫激活中起着重要的作用，但其背后的机制仍然不清楚。在此，我们发现趋化因子CCL5是UC发病机制中免疫调节的核心媒介。本课题利用不同背景的CCL5缺失（CCL5 KO）小鼠，构建DSS诱导的UC模型，通过疾病表型摸索，证明了在KO组小鼠中IL-33诱导的Treg极化受损，而其迁移能力没有受到明显影响，从而导致DSS诱导的肠道炎症恶化。此外，在临床UC患者标本中，CCL5的高水平与FoxP3表达水平呈正相关。机制上，CCL5通过激活CD4+T细胞内JAK/STAT1通路，调节IL33/ST2诱导的FOXP3+ Treg细胞极化，进而抑制UC进展。此外，外源性CCL5可以显著缓解DSS诱导UC小鼠模型的肠道上皮损伤和免疫细胞浸润，进一步证明了UC小鼠模型中CCL5的缺乏导致的结肠炎加重。最后，本课题建立人IBD类器官培养平台，并实现类器官与CCL5预处理的免疫细胞共培养，进一步明确了CCL5是Treg极化中的一个新的免疫调节因子，并提示CCL5蛋白是治疗UC的一个有前途的治疗策略。