Snyder Institute of Infection, Immunity, and Inflammation, Liver Unit, Department of Medicine, University of Calgary, Alberta, Canada.
Am J Physiol Gastrointest Liver Physiol. 2011 Nov;301(5):G749-61. doi: 10.1152/ajpgi.00184.2011. Epub 2011 Aug 25.
It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including chronic inflammatory liver diseases, are associated with changes in central neural transmission that result in alterations in behavior. These behavioral changes include sickness behaviors, such as fatigue, cognitive dysfunction, mood disorders, and sleep disturbances. While such behaviors have a significant impact on quality of life, the changes within the brain and the communication pathways between the liver and the brain that give rise to changes in central neural activity are not fully understood. Traditionally, neural and humoral communication pathways have been described, with the three cytokines TNFα, IL-1β, and IL-6 receiving the most attention in mediating communication between the periphery and the brain, in the setting of peripheral inflammation. However, more recently, we described an immune-mediated communication pathway in experimentally induced liver inflammation whereby, in response to activation of resident immune cells in the brain (i.e., the microglia), peripheral circulating monocytes transmigrate into the brain, leading to development of sickness behaviors. These signaling pathways drive changes in behavior by altering central neurotransmitter systems. Specifically, changes in serotonergic and corticotropin-releasing hormone neurotransmission have been demonstrated and implicated in liver inflammation-associated sickness behaviors. Understanding how the liver communicates with the brain in the setting of chronic inflammatory liver diseases will help delineate novel therapeutic targets that can reduce the burden of symptoms in patients with liver disease.
越来越明显的是，包括慢性炎症性肝病在内的外周器官中心炎症性疾病与中枢神经传递的变化有关，这些变化会导致行为改变。这些行为变化包括疾病行为，如疲劳、认知功能障碍、情绪障碍和睡眠障碍。虽然这些行为对生活质量有重大影响，但导致中枢神经活动变化的大脑内部变化和肝脏与大脑之间的通讯途径尚不完全清楚。传统上，已经描述了神经和体液通讯途径，其中 TNFα、IL-1β 和 IL-6 这三种细胞因子在介导外周炎症中，外周和大脑之间的通讯方面受到了最多的关注。然而，最近我们描述了一种在实验性诱导的肝脏炎症中存在的免疫介导的通讯途径，其中，大脑中固有免疫细胞（即小胶质细胞）的激活，外周循环中的单核细胞迁移到大脑中，导致疾病行为的发生。这些信号通路通过改变中枢神经递质系统来驱动行为的变化。具体来说，已经证明了 5-羟色胺能和促肾上腺皮质激素释放激素神经传递的变化，并与肝脏炎症相关的疾病行为有关。了解肝脏在慢性炎症性肝病中的与大脑通讯的方式将有助于确定新的治疗靶点，从而减轻肝病患者的症状负担。
