The role of TWEAK and Fn14 in the Pathogenesis and Treatment of Neuropsychiatric

描述(申请人提供)：系统性红斑狼疮(SLE)是一种全身性自身免疫性疾病，神经精神损害的发生率很高。神经精神性系统性红斑狼疮(NPSLE)的体征和症状是狼疮患者最早和最常见的表现之一，可以独立于非神经系统疾病发生。在MRL/LPR品系中，也是一种常用的小鼠狼疮模型，在自身抗体效价升高和其他主要器官受累之前，幼年动物出现了与严重抑郁和认知障碍相一致的行为变化。这些研究和其他研究表明，NPSLE确实是一种主要的疾病表现。然而，尽管NPSLE的发病率很高，预后也很差，但其发病机制尚不清楚，最佳治疗方法仍不清楚。以前的研究主要集中在潜在的致病因素上，如自身抗体和神经变性，这些因素通常在SLE发病后相对较晚才显现出来。这些因素不能充分解释在狼疮小鼠或许多患者中观察到的NPSLE的早期发病。在早期中枢神经系统功能障碍的可能调节因子中，细胞因子可以通过一系列不同的机制直接或间接促进中枢神经系统的负性结局。这些包括对自身抗体的影响，细胞因子和其他炎症介质的分泌增加，血脑屏障(BBB)完整性的丧失，以及 神经递质代谢。肿瘤坏死因子超家族成员在系统性红斑狼疮的发病机制中起重要作用。TWINE是这个细胞因子超家族中的一个分泌型成员，对多种类型的细胞具有趋化作用，包括促进炎症和对细胞存活和凋亡的上下文依赖效应。TWAKE受体Fn14表达于星形胶质细胞、小胶质细胞、脑微血管内皮细胞和神经元。此外，TWAKE还可诱导其他已知在NPSLE中起作用的炎性细胞因子的释放。最近，我们发现Fn14缺乏的MRL/LPR狼疮小鼠表现出的抑郁和认知异常明显少于Fn14充足的MRL/LPR小鼠，而人类NPSLE与脑脊液中高水平的调整有关。我们的初步研究有力地支持了这样的假设：1)TWAKE在NPSLE的病因中起主要作用；2)TWEK阻断可能是治疗神经精神疾病的一种新方法。在这项研究中，我们将确认TWEE在NPSLE发病机制中的作用，研究TWEK信号诱导狼疮神经行为异常的机制，并研究TWEE抑制对NPSLE临床表现的治疗潜力。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a high incidence of neuropsychiatric involvement. Signs and symptoms of neuropsychiatric SLE (NPSLE) are among the earliest and most common manifestations in lupus patients, and can occur independently of non-neurologic disease. In the MRL/lpr strain as well, a commonly used murine lupus model, behavioral changes consistent with severe depression and impaired cognition are evident in young animals before increased autoantibody titers and other major organ involvement. These and other studies indicate that NPSLE is indeed a primary disease manifestation. Nevertheless, despite the high prevalence of NPSLE and its poor prognosis, the pathogenesis is not well understood and optimal treatment is still unclear. Previous studies have largely focused on potential etiological factors such as autoantibodies and neurodegeneration that often become apparent only relatively late after onset of SLE. These factors do not adequately explain the early onset of NPSLE observed in lupus mice or in many patients. Among putative regulators of early CNS dysfunction, cytokines can both directly and indirectly promote negative CNS outcomes via a range of different mechanisms. These include effects on autoantibodies, increasing secretion of cytokines and other inflammatory mediators, loss of integrity of the blood brain barrier (BBB), and alteration of neurotransmitter metabolism. Members of the TNF superfamily are important in the pathogenesis of SLE. TWEAK is a secreted member of this cytokine superfamily, with pleotropic effects on multiple cell types, including promotion of inflammation and context-dependent effects on cell survival and apoptosis. The TWEAK receptor, Fn14, is expressed in astrocytes, microglia, brain microvascular endothelial cells, and neurons. Furthermore, TWEAK induces the release of other inflammatory cytokines known to play a role in NPSLE. Recently, we found that Fn14 deficient MRL/lpr lupus mice display significantly less depression and cognitive abnormalities than Fn14 sufficient MRL/lpr littermates, while human NPSLE is associated with high TWEAK levels in the CSF. Our preliminary studies strongly support the hypotheses that 1) TWEAK plays a major role in the etiology of NPSLE; 2) TWEAK blockade may be a novel approach for the treatment of neuropsychiatric disease. In this proposal, we will confirm the role of TWEAK in the pathogenesis of NPSLE, examine the mechanisms by which TWEAK signaling induces neurobehavioral abnormalities in lupus, and study the therapeutic potential of TWEAK inhibition for treating manifestations of NPSLE.