Department of Pathology, University of Alabama at Birmingham, Birmingham, AL.
Department of Surgery, Neuroscience, and Neurology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL.
J Immunol. 2022 Apr 15;208(8):2054-2066. doi: 10.4049/jimmunol.2100869. Epub 2022 Apr 4.
Neurobehavioral disorders and brain abnormalities have been extensively reported in both Crohn's disease and ulcerative colitis patients. However, the mechanism causing neuropathological disorders in inflammatory bowel disease patients remains unknown. Studies have linked the Th17 subset of CD4 T cells to brain diseases associated with neuroinflammation and cognitive impairment, including multiple sclerosis, ischemic brain injury, and Alzheimer's disease. To better understand how CD4 T lymphocytes contribute to brain pathology in chronic intestinal inflammation, we investigated the development of brain inflammation in the T cell transfer model of chronic colitis. Our findings demonstrate that CD4 T cells infiltrate the brain of colitic mice in proportional levels to colitis severity. Colitic mice developed hypothalamic astrogliosis that correlated with neurobehavioral disorders. Moreover, the brain-infiltrating CD4 T cells expressed Th17 cell transcription factor retinoic acid-related orphan receptor γt (RORγt) and displayed a pathogenic Th17 cellular phenotype similar to colonic Th17 cells. Adoptive transfer of RORγt-deficient naive CD4 T cells failed to cause brain inflammation and neurobehavioral disorders in recipients, with significantly less brain infiltration of CD4 T cells. The finding is mirrored in chronic dextran sulfate sodium-induced colitis in mice that showed lower frequency of brain-infiltrating CD4 T cells and astrogliosis despite onset of significantly more severe colitis compared with wild-type mice. These findings suggest that pathogenic RORγtCD4 T cells that aggravate colitis migrate preferentially into the brain, contributing to brain inflammation and neurobehavioral disorders, thereby linking colitis severity to neuroinflammation.
神经行为障碍和大脑异常在克罗恩病和溃疡性结肠炎患者中都有广泛报道。然而，导致炎症性肠病患者神经病理障碍的机制尚不清楚。研究将 CD4 T 细胞的 Th17 亚群与与神经炎症和认知障碍相关的脑疾病联系起来，包括多发性硬化症、缺血性脑损伤和阿尔茨海默病。为了更好地了解 CD4 T 淋巴细胞如何导致慢性肠道炎症中的脑病理学，我们研究了慢性结肠炎 T 细胞转移模型中脑炎症的发展。我们的研究结果表明，CD4 T 细胞以与结肠炎严重程度成比例的水平浸润结肠炎小鼠的大脑。患有结肠炎的小鼠发生下丘脑星形胶质细胞增生，与神经行为障碍相关。此外，脑浸润的 CD4 T 细胞表达 Th17 细胞转录因子维甲酸相关孤儿受体 γt（RORγt），并表现出与结肠 Th17 细胞相似的致病性 Th17 细胞表型。过继转移缺乏 RORγt 的幼稚 CD4 T 细胞未能在受体中引起脑炎症和神经行为障碍，CD4 T 细胞的脑浸润明显减少。这一发现反映在慢性葡聚糖硫酸钠诱导的结肠炎中，与野生型小鼠相比，尽管结肠炎的严重程度明显增加，但小鼠中脑浸润的 CD4 T 细胞和星形胶质细胞增生的频率较低。这些发现表明，加重结肠炎的致病性 RORγtCD4 T 细胞优先迁移到大脑，导致脑炎症和神经行为障碍，从而将结肠炎的严重程度与神经炎症联系起来。
