MDSC在维持IBD肠免疫稳态中的作用及其机制

Inflammatory bowel disease (IBD) is characterized by chronic, persistent and recurrent inflammation, the underlying mechanisms of which need be further elucidated. Myeloid-derived suppressor cells (MDSC) are a subset of immature cells with anti-inflammatory function, the role of which in maintaining intestinal immune homeostasis are still unclear. Our previous study showed that TLR2 signal could induce the differentiation of MDSCs to pro-inflammatory cells and block MDSC-mediated T cell suppression. Meanwhile, using intestinal bacteria spectrum analysis, we observed the excessive activation of TLR signals in IBD mice model. And TLRs agonists could aggravate the inflammation along with the decreased MDSC and increased pro-inflammatory cytokines. Since it has been found that the MDSC number is increased greatly in the peripheral blood of IBD patients and colitis mice, but they fail to stop the progression of IBD. We suspect that MDSC differentiation by the induction of TLR2 signal might play a key role in IBD. Therefore, colitis mice and IBD patients are as models. Metagenomics are used to identify gut bacteria of inducing TLR signal excessive activation; TLR-/- and transgenic mice models are used to confirm the reversion of MDSC by TLR signal; and proteomics are used to screen the key pathway involved in the mechanisms of TLR signal reversing MDSC. The expected results might clarify the causes of IBD, and provide a new perspective for the reconstruction of intestinal immune homeostasis.

炎症性肠病（IBD）慢性炎症迁延不愈的机制远未阐明。髓系来源的抑制性细胞（MDSC）是一群具抑炎功能的未成熟细胞，其在维持肠免疫稳态中的作用尚待阐释。我们前期发现，MDSC可被TLR2信号诱导分化，由抑炎转为促炎。同时我们分析肠道菌谱发现，IBD时肠局部Toll信号过度活化，且TLRs激动剂体内作用可加重肠炎，并伴有肠局部MDSC减少和炎性因子大量产生。结合已知的MDSC在IBD患者和肠炎小鼠外周血中显著增多，却未能阻止炎症进程，我们推测：Toll信号诱导MDSC逆转为促炎细胞，是否是IBD迁延不愈的关键？基于此，本研究拟以肠炎小鼠和IBD患者为模型，宏基因组学鉴定IBD中过度激活Toll信号的差异菌群；基于TLRs-/-和转基因鼠明确Toll信号逆转MDSC抑炎功能；蛋白组学筛选Toll信号逆转MDSC的关键通路。预期成果有望阐明IBD迁延不愈的机制，为重建肠道免疫稳态提供新视角。

炎症性肠病（IBD）慢性炎症迁延不愈的机制远未阐明。髓系来源的抑制性细胞（MDSC）是一群具抑炎功能的未成熟细胞，其在维持肠免疫稳态中的作用尚待阐明。因此，本项目基于IBD患者和肠炎小鼠模型，以MDSC为研究对象，利用代谢组学、3D免疫荧光、高参数流式、基因敲除等先进技术，研究了MDSC在IBD中维持肠免疫稳态的关键作用及相关调控机制。结果发现，IBD中单核样MDSC（M-MDSC）和多形核样MDSC（PMN-MDSC）浸润均显著增多，但仍未能阻止肠道炎症进展。同时发现，肠炎微环境存在乙酰胆碱（ACh）等神经递质减少，菌群相关代谢物色氨酸（TRP）等代谢紊乱，以及菌群相关Toll信号增强的特征性改变。进一步，揭示了ACh增强M-MDSC抑炎功能的新机制，TRP促进PMN-MDSC损伤修复功能的新机制，以及Toll信号减弱M-MDSC抑制功能的新机制。更为重要的是，靶向MDSC的上述神经免疫和代谢免疫调控通路，可有效缓解肠道炎症和疾病进程。因此，该研究成果以IBD中MDSC抑炎功能受损机制为切入点，拓展了对肠区神经免疫和代谢免疫调控机制的认识与理解，更为研发基于神经免疫、代谢免疫调控的IBD临床防治新策略提供理论和实验基础。

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