IKBKE contributes to neuropsychiatric manifestations in lupus-prone mice through microglial activation.
IKBKE contributes to neuropsychiatric manifestations in lupus-prone mice through microglial activation.
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IKBKE 通过小胶质细胞激活导致狼疮易感小鼠的神经精神表现。
DOI：
10.1002/art.42352
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Atsumi T
中科院分区：
文献类型：
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作者：
Karino K;Kono M;Takeyama S;Kudo Y;Kanda M;Abe N;Aso K;Fujieda Y;Kato M;Oku K;Amengual O;Atsumi T
目的系统性红斑狼疮(SLE)是一种以多器官功能障碍为特征的系统性自身免疫性疾病。神经精神性系统性红斑狼疮(NPSLE)占狼疮患者的30-40%，是SLE最严重的临床表现，常导致日常生活能力受限。最近的研究表明，小胶质细胞是中枢神经系统中的组织驻留巨噬细胞，参与了NPSLE的发病机制。本研究旨在探索治疗NPSLE的新靶点。方法对MRL/LPR、狼疮易感小鼠的小胶质细胞和体外培养的小胶质细胞进行RNA测序。我们发现了一个可作为NPSLE治疗靶点的候选基因，并利用特异性抑制剂和小干扰RNA研究了其在小胶质细胞活化和吞噬功能中的作用。结果转录组学分析显示，体外培养的mRL/lpr小鼠和细胞因子刺激的小胶质细胞中，编码核因子κB激酶亚单位ɛ(iKBKε)抑制物的IKBKE基因表达上调。脑室内给予IKBKε抑制剂可改善mrl/lpr鼠的认知功能并抑制小胶质细胞的激活。从机制上讲，抑制IKBKε可减少糖酵解，从而抑制小胶质细胞的活化和吞噬功能。结论IKBKε通过激活小胶质细胞在NPSLE的发病机制中起重要作用，可作为治疗NPSLE的靶点。
ObjectiveSystemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiorgan dysfunction. Neuropsychiatric SLE (NPSLE) occurs in 30–40% of lupus patients and is the most severe presentation of SLE, frequently resulting in limitation of daily life. Recent studies have shown that microglia, tissue‐resident macrophages in the central nervous system, are involved in the pathogenesis of NPSLE. This study was undertaken to explore new therapeutic targets for NPSLE focusing on microglia.MethodsRNA sequencing of microglia in MRL/lpr, lupus‐prone mice, as well as that of microglia cultured in vitro with cytokines were performed. A candidate gene, which could be a therapeutic target for NPSLE, was identified, and its role in microglial activation and phagocytosis was investigated using specific inhibitors and small interfering RNA. The effect of intracerebroventricular administration of the inhibitor on the behavioral abnormalities of MRL/lprwas also evaluated.ResultsTranscriptome analysis revealed the up‐regulation ofIkbke, which encodes the inhibitor of NF‐κB kinase subunit ɛ (IKBKε) in both microglia from MRL/lprmice and cytokine‐stimulated microglia in vitro. Intracerebroventricular administration of an IKBKε inhibitor ameliorated cognitive function and suppressed microglial activation in MRL/lprmice. Mechanistically, IKBKε inhibition reduced glycolysis, which dampened microglial activation and phagocytosis.ConclusionThese findings suggest that IKBKε plays a vital role in the pathogenesis of NPSLE via microglial activation, and it could serve as a therapeutic target for NPSLE.