Farncombe Family Digestive Health Research Institute, Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada.
Inflamm Bowel Dis. 2011 Jul;17(7):1474-89. doi: 10.1002/ibd.21531. Epub 2011 Jan 18.
Depression is common in patients with inflammatory bowel disease (IBD) but the pathway is not well understood. We examined whether the locus of susceptibility to colitis in mice with depression-like behavior (DLB) resides with the macrophage and implicates the vagus nerve.
Chronic colitis mimicking ulcerative colitis (UC) was induced by dextran sulfate sodium administered to C57BL/6-mice. Depression was induced by intracerebroventricular infusion of reserpine in healthy or vagotomized mice treated with antidepressant desmethylimipramine (DMI). Colitis was assessed macroscopically, histologically, and by C-reactive protein measurement in serum and by cytokines in colonic samples. Cytokine release was measured on macrophages isolated from these models. Naive macrophage colony-stimulating factor-deficient mice (op/op) were injected with peritoneal macrophages obtained from the different groups and acute colitis was induced.
Vagotomy reactivated inflammation in mice with chronic colitis. DLB reactivated colitis and this was prevented by DMI only in mice with intact vagi. Macrophages isolated from vagotomized or DLB-mice showed a selective increase of proinflammatory cytokine release and this was not seen in macrophages isolated from DLB-DMI-treated mice; moreover, vagotomy abolished this beneficial effect. In op/op, adoptive transfer of macrophages from non-DLB mice significantly increased the inflammatory markers. These parameters were significantly increased when transferred with macrophages isolated from DLB or VXP mice. Op/op mice that received macrophages from DLB-DMI-treated mice showed a significant decrease of all parameters and vagotomy abolished this effect.
These data identify the critical role of macrophage in linking depression and susceptibility to intestinal inflammation via the vagus nerve. The results provide a basis for developing new approaches to the management of UC patients with coexisting depression by rebalancing cytokine production by the cell.
抑郁在炎症性肠病（IBD）患者中很常见，但发病机制尚不清楚。我们研究了具有抑郁样行为（DLB）的小鼠中结肠炎易感性的病灶是否与巨噬细胞有关，并暗示了迷走神经的作用。
通过给予 C57BL/6 小鼠葡聚糖硫酸钠，模拟溃疡性结肠炎（UC）诱导慢性结肠炎。在接受抗抑郁药去甲丙咪嗪（DMI）治疗的健康或迷走神经切断的小鼠中，通过脑室内注射利血平诱导抑郁。通过宏观、组织学和血清 C-反应蛋白测量以及结肠样本中的细胞因子评估结肠炎。从小鼠模型中分离出巨噬细胞后，测量细胞因子的释放。将不同组的腹腔巨噬细胞注射到幼稚的巨噬细胞集落刺激因子缺陷小鼠（op/op）中，诱导急性结肠炎。
迷走神经切断术可使慢性结肠炎小鼠的炎症重新激活。DLB 可使结肠炎重新激活，而在迷走神经完整的小鼠中，DMI 仅能预防这种作用。从迷走神经切断或 DLB 小鼠中分离出的巨噬细胞表现出促炎细胞因子释放的选择性增加，而在从 DLB-DMI 治疗的小鼠中分离出的巨噬细胞中则没有观察到这种情况；此外，迷走神经切断术消除了这种有益作用。在 op/op 中，非 DLB 小鼠的巨噬细胞的过继转移显著增加了炎症标志物。当用来自 DLB 或 VXP 小鼠的巨噬细胞进行转移时，这些参数显著增加。接受来自 DLB-DMI 治疗的小鼠的巨噬细胞的 op/op 小鼠表现出所有参数的显著下降，而迷走神经切断术消除了这种作用。
这些数据表明，巨噬细胞通过迷走神经在将抑郁与对肠道炎症的易感性联系起来方面发挥着关键作用。这些结果为通过重新平衡细胞因子产生来开发治疗同时患有 UC 和抑郁的患者的新方法提供了依据。
