Abstract：
BACKGROUND: Inflammatory bowel disease (IBD) is a chronic and relapsing disease characterized by immune-mediated dysfunction of intestinal homeostasis. Alteration of the enteric nervous system and the subsequent neuro-immune interaction are thought to contribute to the initiation and progression of IBD. However, the role of dopamine beta-hydroxylase (DBH), an enzyme converting dopamine into norepinephrine, in modulating intestinal inflammation is not well defined.
METHODS: CD4+CD45RBhighT cell adoptive transfer, and 2,4-dinitrobenzene sulfonic acid (DNBS) or dextran sodium sulfate (DSS)-induced colitis were collectively conducted to uncover the effects of DBH inhibition by nepicastat, a DBH inhibitor, in mucosal ulceration, disease severity, and T cell function.
RESULTS: Inhibition of DBH by nepicastat triggered therapeutic effects on T cell adoptive transfer induced chronic mouse colitis model, which was consistent with the gene expression of DBH in multiple cell populations including T cells. Furthermore, DBH inhibition dramatically ameliorated the disease activity and colon shortening in chemically induced acute and chronic IBD models, as evidenced by morphological and histological examinations. The reshaped systemic inflammatory status was largely associated with decreased pro-inflammatory mediators, such as TNF-α, IL-6 and IFN-γ in plasma and re-balanced Th1, Th17 and Tregs in mesenteric lymph nodes (MLNs) upon colitis progression. Additionally, the conversion from dopamine (DA) to norepinephrine (NE) was inhibited resulting in increase in DA level and decrease in NE level and DA/NE showed immune-modulatory effects on the activation of immune cells.
CONCLUSIONS: Modulation of neurotransmitter levels via inhibition of DBH exerted protective effects on progression of murine colitis by modulating the neuro-immune axis. These findings suggested a promising new therapeutic strategy for attenuating intestinal inflammation.
METHODS: CD4+CD45RBhighT cell adoptive transfer, and 2,4-dinitrobenzene sulfonic acid (DNBS) or dextran sodium sulfate (DSS)-induced colitis were collectively conducted to uncover the effects of DBH inhibition by nepicastat, a DBH inhibitor, in mucosal ulceration, disease severity, and T cell function.
RESULTS: Inhibition of DBH by nepicastat triggered therapeutic effects on T cell adoptive transfer induced chronic mouse colitis model, which was consistent with the gene expression of DBH in multiple cell populations including T cells. Furthermore, DBH inhibition dramatically ameliorated the disease activity and colon shortening in chemically induced acute and chronic IBD models, as evidenced by morphological and histological examinations. The reshaped systemic inflammatory status was largely associated with decreased pro-inflammatory mediators, such as TNF-α, IL-6 and IFN-γ in plasma and re-balanced Th1, Th17 and Tregs in mesenteric lymph nodes (MLNs) upon colitis progression. Additionally, the conversion from dopamine (DA) to norepinephrine (NE) was inhibited resulting in increase in DA level and decrease in NE level and DA/NE showed immune-modulatory effects on the activation of immune cells.
CONCLUSIONS: Modulation of neurotransmitter levels via inhibition of DBH exerted protective effects on progression of murine colitis by modulating the neuro-immune axis. These findings suggested a promising new therapeutic strategy for attenuating intestinal inflammation.
摘要：
背景：炎症性肠病（IBD）是一种以免疫介导的肠稳态功能障碍为特征的慢性复发性疾病。肠神经系统的改变和随后的神经-免疫相互作用被认为有助于IBD的开始和进展。然而,多巴胺β-羟化酶（DBH）的作用，一种将多巴胺转化为去甲肾上腺素的酶，在调节肠道炎症方面还没有很好的定义。
方法：CD4+CD45RBhighT细胞过继转移，和2,4-二硝基苯磺酸（DNBS）或葡聚糖硫酸钠（DSS）诱导的结肠炎共同进行，以揭示内匹卡司他对DBH的抑制作用，DBH抑制剂，粘膜溃疡，疾病严重程度,和T细胞功能。
结果：nepicastat抑制DBH对T细胞过继性转移诱导的慢性小鼠结肠炎模型的治疗作用，这与包括T细胞在内的多个细胞群体中DBH的基因表达一致。此外，在化学诱导的急性和慢性IBD模型中，DBH抑制显着改善了疾病活动和结肠缩短，形态学和组织学检查证明。重塑的全身炎症状态在很大程度上与降低的促炎介质有关，如TNF-α，结肠炎进展时血浆中的IL-6和IFN-γ以及肠系膜淋巴结(MLN)中的Th1、Th17和Treg再平衡。此外,多巴胺（DA）向去甲肾上腺素（NE）的转化受到抑制，导致DA水平升高和NE水平降低，DA/NE对免疫细胞的激活具有免疫调节作用。
结论：通过抑制DBH调节神经递质水平通过调节神经免疫轴对小鼠结肠炎的进展具有保护作用。这些发现表明了一种有希望的减轻肠道炎症的新治疗策略。
方法：CD4+CD45RBhighT细胞过继转移，和2,4-二硝基苯磺酸（DNBS）或葡聚糖硫酸钠（DSS）诱导的结肠炎共同进行，以揭示内匹卡司他对DBH的抑制作用，DBH抑制剂，粘膜溃疡，疾病严重程度,和T细胞功能。
结果：nepicastat抑制DBH对T细胞过继性转移诱导的慢性小鼠结肠炎模型的治疗作用，这与包括T细胞在内的多个细胞群体中DBH的基因表达一致。此外，在化学诱导的急性和慢性IBD模型中，DBH抑制显着改善了疾病活动和结肠缩短，形态学和组织学检查证明。重塑的全身炎症状态在很大程度上与降低的促炎介质有关，如TNF-α，结肠炎进展时血浆中的IL-6和IFN-γ以及肠系膜淋巴结(MLN)中的Th1、Th17和Treg再平衡。此外,多巴胺（DA）向去甲肾上腺素（NE）的转化受到抑制，导致DA水平升高和NE水平降低，DA/NE对免疫细胞的激活具有免疫调节作用。
结论：通过抑制DBH调节神经递质水平通过调节神经免疫轴对小鼠结肠炎的进展具有保护作用。这些发现表明了一种有希望的减轻肠道炎症的新治疗策略。
