肠系膜脂肪通过IL-17诱导肠上皮间质化参与克罗恩病肠道纤维化的研究

Intestinal fibrosis is a tough issue in the treatment of complications from Crohn's disease, previous studies suggested that intestinal fibrosis related closely to the hypertrophic mesenteric fat in Crohn's disease, but the precise mechanism remains unclear. In our clinical experience we found that IL-17 was abnormally elevated in hypertrophic mesenteric fat in Crohn's disease compared with normal fat and IL-17 induce intestinal cell line epithelial mesenchymal transitions (EMT) in vitro, while EMT is an important phase in the process of organ fibrosis. Therefore, it is hypothesized that IL-17 may be the mediator during the involvement of mesenteric fat in the intestinal fibrosis of Crohn's disease. To prove this, we intend to utilizing specimens of from patients with Crohn’s disesae and mice model of intestinal fibrosis to explore the relationship between IL-17 and intestinal fibrosis and the impart of proinflammatory immune microenvironment consist of IL-6/TNF-α/LPS on the concentration of IL-17 in mesenteric fat; explore the impart of IL-17 on the EMT of intestinal epithelial and its upstream pathway NFκB signal. As a result, we will expose the relationship between IL-17 and NFκB signal in the intestinal fibrosis of Crohn's disease and reveal the role of hypertrophy of mesenteric fat in the process of intestine fibrosis and inside potential molecular mechanisms, which will provide with inspiration of clinical research for the prevention and treatment in the Crohn's disease intestinal fibrosis.

肠道纤维性狭窄是克罗恩病治疗中的难点，既往研究提示克罗恩病肠壁纤维化与肠系膜脂肪肥厚密切相关，但具体机制未完全明确。申请者在临床研究中发现IL-17在克罗恩病肥厚的肠系膜脂肪中异常升高，并可促进肠上皮细胞间质化（EMT），而EMT正是器官纤维化的重要阶段，提示IL-17极有可能是肠系膜脂肪参与克罗恩病肠壁纤维化进程的重要介质。为阐明这一机理，本项目拟利用克罗恩病肠系膜标本和小鼠肠道纤维化模型，探讨IL-17与肠壁纤维化指标的相关性和由IL-6/TNF-α/LPS构成的促炎微环境对肠系膜脂肪中IL-17浓度的影响；分析IL-17对肠上皮EMT及其上游NFκB信号的影响，进而明确IL-17与NFκB信号在克罗恩病肠壁纤维化中的关系与作用，借此揭示肥厚肠系膜脂肪在肠壁纤维化中的作用及潜在分子机制。研究结果可为预防和治疗狭窄型克罗恩病提供新的临床研究方向。

MEG3在多种免疫性疾病中起到抑制炎症、阻止纤维化的作用，但在肠道纤维化中的作用与机制，仍需进一步探索。在前期研究的基础上，我们分析对比了克罗恩病病变肠管肥厚肠系膜脂肪与正常肠管肠系膜脂肪的lnc RNA表达情况，发现了lnc RNA MEG3在肥厚肠系膜脂肪中表达下调；利用已建立的克罗恩病肠系膜脂肪干细胞原代细胞系和肠系膜淋巴结悬液共培养体系，我们发现克罗恩病促炎免疫微环境可下调肠系膜脂肪细胞中lnc RNA MEG3的表达。我们目前的结果提示：抑制肠系膜脂肪中MEG3的表达，可能是克罗恩病免疫微环境调节肠系膜脂肪细胞进而促进肠道纤维化的机制之一。