PDF(Pubmed)
Abstract：
The search for dementia treatments, including treatments for neuropsychiatric lupus (NPSLE), has not yet uncovered useful therapeutic targets that mitigate underlying inflammation. Currently, NPSLE\'s limited treatment options are often accompanied by severe toxicity. Blocking toll-like receptor (TLR) and IL-1 receptor signal transduction by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4) offers a new pathway for intervention. Using a pre-clinical NPSLE model, we compare lupus-like B6.MRL-Faslpr (MRL) mice with B6.MRL-Faslpr-IRAK4 kinase-dead (MRL-IRAK4-KD) mice, which are were less prone to \'general\' lupus-like symptoms. We demonstrate that lupus-prone mice with a mutation in the kinase domain of IRAK4 no longer display typical lupus hallmarks such as splenomegaly, inflammation, production of hormones, and anti-double-stranded (ds)DNA antibody. water maze behavioral testing, which measures contextual associative learning, revealed that mice without functional IRAK4 displayed a recovery in memory acquisition deficits. RNA-seq approach revealed that cytokine and hormone signaling converge on the JAK/STAT pathways in the mouse hippocampus. Ultimately, the targets identified in this work may result in broad clinical value that can fill the significant scientific and therapeutic gaps precluding development of cures for dementia.
摘要：
寻找痴呆症治疗方法，包括神经精神狼疮（NPSLE）的治疗，尚未发现缓解潜在炎症的有用治疗靶标。目前,NPSLE有限的治疗选择往往伴随着严重的毒性。通过抑制白细胞介素-1受体相关激酶4（IRAK4）阻断Toll样受体（TLR）和IL-1受体信号转导为干预提供了新的途径。使用临床前NPSLE模型，我们比较狼疮样B6。具有B6的MRL-Faslpr(MRL)小鼠。MRL-Faslpr-IRAK4激酶死亡（MRL-IRAK4-KD）小鼠，它们不太容易出现狼疮样症状。我们证明，IRAK4激酶结构域突变的狼疮易感小鼠不再表现出典型的狼疮标志，如脾肿大，炎症,激素的产生，和抗双链(ds)DNA抗体。水迷宫行为测试，衡量情境联想学习，显示没有功能性IRAK4的小鼠在记忆获取缺陷方面表现出恢复。RNA-seq方法揭示细胞因子和激素信号在小鼠海马中的JAK/STAT途径上收敛。最终,这项工作中确定的目标可能会产生广泛的临床价值，可以填补阻碍痴呆症治疗方法发展的重大科学和治疗空白。
