Patients with chronic inflammatory disorders such as inflammatory bowel disease frequently experience neurological complications including epilepsy, depression, attention deficit disorders, migraines, and dementia. However, the mechanistic basis for these associations is unknown. Given that many patients are unresponsive to existing medications or experience debilitating side effects, novel therapeutics that target the underlying pathophysiology of these conditions are urgently needed. Because intestinal disorders such as inflammatory bowel disease are robustly associated with neurological symptoms, we used three different mouse models of colitis to investigate the impact of peripheral inflammatory disease on the brain. We assessed neuronal hyperexcitability, which is associated with many neurological symptoms, by measuring seizure threshold in healthy and colitic mice. We profiled the neuroinflammatory phenotype of colitic mice and used depletion and neutralization assays to identify the specific mediators responsible for colitis-induced neuronal hyperexcitability. To determine whether our findings in murine models overlapped with a human phenotype, we performed gene expression profiling, pathway analysis, and deconvolution on microarray data from hyperexcitable human brain tissue from patients with epilepsy. We observed that murine colitis induces neuroinflammation characterized by increased pro-inflammatory cytokine production, decreased tight junction protein expression, and infiltration of monocytes and neutrophils into the brain. We also observed sustained neuronal hyperexcitability in colitic mice. Colitis-induced neuronal hyperexcitability was ameliorated by neutrophil depletion or TNFα blockade. Gene expression profiling of hyperexcitable brain tissue resected from patients with epilepsy also revealed a remarkably similar pathology to that seen in the brains of colitic mice, including neutrophil infiltration and high TNFα expression. Our results reveal neutrophils and TNFα as central regulators of neuronal hyperexcitability of diverse etiology. Thus, there is a strong rationale for evaluating anti-inflammatory agents, including clinically approved TNFα inhibitors, for the treatment of neurological and psychiatric symptoms present in, and potentially independent of, a diagnosed inflammatory disorder.

中文翻译：

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小鼠结肠炎和人类癫痫的大脑分析揭示中性粒细胞和 TNFα 作为神经元过度兴奋的介质


患有慢性炎症性疾病（例如炎症性肠病）的患者经常会出现神经系统并发症，包括癫痫、抑郁症、注意力缺陷障碍、偏头痛和痴呆。然而，这些关联的机制基础尚不清楚。鉴于许多患者对现有药物没有反应或经历使人衰弱的副作用，因此迫切需要针对这些病症的潜在病理生理学的新疗法。由于炎症性肠病等肠道疾病与神经系统症状密切相关，因此我们使用了三种不同的结肠炎小鼠模型来研究周围炎症性疾病对大脑的影响。我们通过测量健康小鼠和结肠炎小鼠的癫痫阈值来评估与许多神经系统症状相关的神经元过度兴奋性。我们分析了结肠炎小鼠的神经炎症表型，并使用耗竭和中和试验来鉴定导致结肠炎诱导的神经元过度兴奋的特定介质。为了确定我们在小鼠模型中的发现是否与人类表型重叠，我们对来自癫痫患者的过度兴奋的人脑组织的微阵列数据进行了基因表达谱、通路分析和反卷积。我们观察到，小鼠结肠炎会诱发神经炎症，其特征是促炎细胞因子的产生增加、紧密连接蛋白表达减少以及单核细胞和中性粒细胞浸润到大脑中。我们还在结肠炎小鼠中观察到持续的神经元过度兴奋。结肠炎引起的神经元过度兴奋可通过中性粒细胞耗竭或 TNFα 阻断得到改善。 从癫痫患者身上切除的过度兴奋脑组织的基因表达谱也显示出与结肠炎小鼠大脑中所见的病理学非常相似，包括中性粒细胞浸润和高 TNFα 表达。我们的结果揭示了中性粒细胞和 TNFα 作为不同病因的神经元过度兴奋的中枢调节因子。因此，评估抗炎药物（包括临床批准的 TNFα 抑制剂）用于治疗存在于诊断的炎症性疾病中且可能独立于诊断的炎症性疾病的神经和精神症状是有充分理由的。