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Abstract：
Cognitive dysfunction and mood changes are prevalent and especially taxing issues for patients with systemic lupus erythematosus (SLE). Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its cognate receptor Fn14 have been shown to play an important role in neurocognitive dysfunction in murine lupus. We profiled and compared gene expression in the cortices of MRL/+, MRL/lpr (that manifest lupus-like phenotype) and MRL/lpr-Fn14 knockout (Fn14ko) adult female mice to determine the transcriptomic impact of TWEAK/Fn14 on cortical gene expression in lupus. We found that the TWEAK/Fn14 pathway strongly affects the expression level, variability and coordination of the genomic fabrics responsible for neurotransmission and chemokine signaling. Dysregulation of the Phosphoinositide 3-kinase (PI3K)-AKT pathway in the MRL/lpr lupus strain compared with the MRL/+ control and Fn14ko mice was particularly prominent and, therefore, promising as a potential therapeutic target, although the complexity of the transcriptomic fabric highlights important considerations in in vivo experimental models.
摘要：
认知功能障碍和情绪变化是普遍存在的，尤其是系统性红斑狼疮（SLE）患者的问题。肿瘤坏死因子（TNF）样弱凋亡诱导剂（TWEAK）及其同源受体Fn14已被证明在小鼠狼疮的神经认知功能障碍中起重要作用。我们分析并比较了MRL/+皮层中的基因表达，MRL/lpr（表现为狼疮样表型）和MRL/lpr-Fn14敲除（Fn14ko）成年雌性小鼠，以确定TWEAK/Fn14对狼疮中皮质基因表达的转录组影响。我们发现TWEAK/Fn14通路强烈影响表达水平,负责神经传递和趋化因子信号传导的基因组结构的变异性和协调性。与MRL/+对照和Fn14ko小鼠相比，MRL/lpr狼疮品系中磷酸肌醇3-激酶（PI3K）-AKT途径的失调尤为突出，因此,有希望作为潜在的治疗靶点，尽管转录组学结构的复杂性突出了体内实验模型中的重要考虑因素。
