前炎性单核/巨噬细胞活化在抑郁/焦虑恶化炎症性肠病中的相关机制探讨

Lots of evidences have shown that depression/anxiety can aggravate the inflammation of Inflammatory Bowel Disease (IBD). However, the mechanism is not clear yet. Recently, neuroimmunological studies have confirmed that pro-inflammatory monocyte/macrophage plays a key role in the pathogenesis of psychosomatic disease including depression/anxiety. Our previous results have shown that IBD patients with depression/anxiety had more severe symptom and worse therapeutic effect of steroids than the IBD patients without depression/anxiety. At the same time, the level of M1 macrophage cytokines were higher and was positively related to the depression scores. Based on those data, we hypothesize that depression-driving activation of pro-inflammatory monocyte/macrophage may be one of the key factors in how depression/anxiety aggravates IBD. This project will focus on IBD patients with depression/anxiety only, and will use flow cytometry assay, qPCR, Luminex xMAP, immunofluorescence, etc, to investigate the function and phenotypes of pro-inflammatory monocyte/macrophage, the pro-inflammatory monocyte/macrophage-related low-grade systemic inflammation, T cell polarization, and to explore intestinal inflammation, intestinal epithelial barrier, glucocorticoid resistance. We will also confirm the hypnosis in animal studies. We wish to elucidate the immunological mechanism of depression/anxiety worsening IBD, and provide with scientific evidence for treatment of IBD patients with depression/anxiety.

研究表明抑郁/焦虑等负面情绪与炎症性肠病（IBD）关系密切，但其机制尚不清楚。 近年来心理神经免疫学研究示前炎性单核/巨噬细胞可能在抑郁/焦虑等心理精神疾病的发生发展中有重要作用。我们前期研究发现，伴有抑郁/焦虑的IBD患者症状更重，激素治疗效果更差；外周血M1型巨噬细胞生物标志物明显升高，且与抑郁评分呈正相关。因此我们推测抑郁诱导的前炎性单核/巨噬细胞活化，极可能是心理精神因素调节IBD炎症关键环节。本项目拟以伴有抑郁/焦虑症的IBD患者为研究对象，从体内外水平，观察伴抑郁/焦虑症的IBD患者前炎性单核/巨噬细胞的表型与功能，及其所诱导的低度全身性炎症反应和Th细胞分化，分析与此相关的肠道病理改变、肠道上皮细胞屏障和糖皮质激素抵抗机制，同时在动物模型上进一步证实这一假设。希望通过本研究初步阐释抑郁/焦虑等心理精神因素恶化IBD的免疫机制，为伴抑郁/焦虑症IBD特异靶向治疗提供新思路。

研究表明抑郁/焦虑等负面情绪与炎症性肠病（IBD）关系密切，但其机制尚不清楚。近年来心理神经免疫学研究显示前炎性单核/巨噬细胞可能在抑郁/焦虑等心理精神疾病的发生发展中有重要作用。课题组基于前期研究发现提出“焦虑/抑郁通过前炎性单核/巨噬细胞活化恶化炎症性肠病”这一假设，以伴和不伴抑郁/焦虑的IBD患者为研究对象，调查患者的临床特征、单核/巨噬细胞的表型与功能，及其所诱导的低度全身性炎症反应和Th细胞分化，分析与此相关的肠道上皮屏障功能和糖皮质激素抵抗机制，同时在动物模型上进一步证实这一假设。结果显示：①伴焦虑/抑郁的IBD患者病情更重，疾病活动度评分、内镜评分、病理组织学评分与焦虑/抑郁评分呈正相关，伴焦虑/抑郁的IBD患者外周血促炎因子水平更高，且与焦虑/抑郁评分呈正相关。②伴焦虑/抑郁状态的IBD患者外周血单核/巨噬细胞促炎型比例升高，抗炎型比例降低，吞噬功能减弱，且伴焦虑/抑郁状态的IBD患者外周血单核细胞诱导CD4+T细胞向Th1和Th17细胞分化增多，向Treg细胞分化减少。伴焦虑/抑郁的IBD患者巨噬细胞对肠上皮屏障损害更重。③我们在动物模型上验证了上述发现，并发现IRF5调控肠粘膜巨噬细胞向M1型免疫表型极化增强以及促炎因子分泌增多，慢病毒介导shRNA干扰IRF5表达可以通过抑制巨噬细胞向M1型极化改善DSS结肠炎。④伴焦虑/抑郁状态的IBD患者发生激素抵抗的比例更高，外周血单个核细胞糖皮质激素受体α表达减少。这些可能是焦虑/抑郁加重IBD的机制。本研究发现可以为阐明焦虑/抑郁等心理精神疾病与IBD等自身免疫性疾病的相互作用机制提供新思路，为IBD患者临床管理和治疗提供新靶点。