Microglia-dependent synapse loss in type I interferon-mediated lupus (Retracted article. See vol. 578, pg. 177, 2020)
Microglia-dependent synapse loss in type I interferon-mediated lupus (Retracted article. See vol. 578, pg. 177, 2020)
复制标题
DOI：
10.1038/nature22821
复制
发表时间：
2017-06-22
期刊：
影响因子：
64.8
通讯作者：
Carroll, Michael C.
中科院分区：
文献类型：
--
作者：
Bialas, Allison R.;Presumey, Jessy;Carroll, Michael C.
系统性红斑狼疮（SLE）是一种无法治愈的自身免疫性疾病，其特征是自身抗体沉积在肾脏、皮肤和肺等组织中。值得注意的是，高达75%的SLE患者出现神经精神症状，包括焦虑、抑郁、认知障碍和癫痫发作，在极少数情况下，还出现精神病-统称为中枢神经系统（CNS）狼疮（1-4）。在某些情况下，某些自身抗体，如抗NMDAR或抗磷脂抗体（5，6），促进中枢神经系统狼疮。然而，在大多数患者中，这些症状背后的机制尚不清楚。中枢神经系统狼疮通常在狼疮诊断时或在第一年内出现，这表明导致外周自身免疫的早期因素可能促进中枢神经系统狼疮症状。在这里，我们报告的行为表型和突触损失狼疮倾向的小鼠，阻止I型干扰素（IFN）信号。此外，我们表明，I型干扰素刺激小胶质细胞成为反应性和吞噬神经元和突触材料在狼疮易感小鼠。这些发现和我们在SLE患者死后海马脑切片中观察到的I型IFN信号增加，可能指导正在进行的I型IFN受体拮抗剂anifrolumab临床试验的评价（7）。此外，IFN驱动的小胶质细胞依赖性突触丢失的鉴定，沿着小胶质细胞转录组数据，将CNS狼疮与其他CNS疾病联系起来，并为在一些SLE患者中观察到的神经系统症状提供了解释。
Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus(1-4). In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies(5,6), promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab(7), a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.