IRAK4 and Systemic Lupus Erythematosus

摘要 系统性红斑狼疮(SLE)是一种破坏性的自身免疫性疾病，影响500万人 世界各地的人们。通常，系统性红斑狼疮会影响中枢和外周神经系统，这是一种综合征 统称为神经精神系统性红斑狼疮(NPSLE)。认知功能障碍(CD)是一个重要的 NPSLE的问题，据报道影响到广泛的患者，反映了 疾病，缺乏标准的诊断标准，以及需要更多的研究。 越来越多的证据表明Toll样受体(TLRs)参与了SLE的发病 IRAK4是一种关键的信号通路，参与SLE的大多数TLRs的信号传导。通过研究角色 在易患SLE的小鼠中，我们发现狼疮和脑微血管内皮细胞之间存在联系 细胞，重要的是，检测到了与CD相关的特定趋化因子。我们 假设抑制IRAK4活性将通过减少Cd来缓解NPSLE。这将是 通过鉴定狼疮小鼠模型中的细胞和分子脑变化进行测试 IRAK4活性被取消，包括分析大脑和血清趋化因子以及 脑组织激活状态和信号通路的尖端成像质量研究 光谱分析。最后，我们将测试废除IRAK4活动是否会影响CD使用相同的 模特。这些发现将促进我们对NPSLE中IRAK4信号转导的理解，促进 设计减轻CD的药物，为NPSLE患者的翻译研究铺平道路。

Summary Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that affects 5 million people worldwide. Frequently, SLE affects the central and peripheral nervous system, a syndrome collectively named neuropsychiatric SLE (NPSLE). Cognitive dysfunction (CD) is a significant problem in NPSLE that is reported to affect a broad range of patients, reflecting the complexity of the disease, the lack of standard criteria for diagnostics, and the need for additional research. Accumulating evidence demonstrates the involvement of Toll-like receptors (TLRs) in SLE, and IRAK4 is a key kinase that initiates signaling by most TLRs involved in SLE. By studying the role of IRAK4 in SLE prone mice we found a link between lupus and brain microvascular endothelial cells, and importantly, detected specific chemokines that are also associated with CD. We hypothesize that inhibition of IRAK4 activity will alleviate NPSLE by reducing CD. This will be tested by identifying the cellular and molecular brain alterations in a lupus mouse model in which the IRAK4 activity is abolished that include, profiling brain and serum chemokines and also activation states and signaling pathways in brain tissue using cutting-edge Imaging Mass Spectrometry analysis. Lastly, we will test if abolishing IRAK4 activity impacts CD using the same model. These findings will advance our understanding of IRAK4 signaling in NPSLE, facilitate design of drugs to attenuate CD, and pave the way for translational studies in NPSLE patients.