Lipocalin-2 protects the brain during inflammatory conditions.
Lipocalin-2 protects the brain during inflammatory conditions.
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DOI：
10.1038/mp.2016.243
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发表时间：
2018-03
影响因子：
11
通讯作者：
Fryer JD
中科院分区：
文献类型：
--
作者：
Kang SS;Ren Y;Liu CC;Kurti A;Baker KE;Bu G;Asmann Y;Fryer JD
脓毒症是一种常见的健康问题，可导致中枢神经系统（CNS）炎症，并伴有长期的行为和认知改变。使用超过100种不同细胞因子的无偏蛋白质组学分析，我们发现脂质运载蛋白-2（LCN 2）是外周给予脂多糖（LPS）后CNS中最显著升高的蛋白质。为了确定中枢神经系统中高水平的LCN 2是保护性的还是有害的，我们用外周LPS攻击LCN 2 −/−小鼠，并确定其对行为和神经炎症的影响。在对应于注射LPS的野生型（WT）小鼠中的峰值LCN 2诱导的时间，用LPS激发的Lcn 2 −/−小鼠的促炎细胞因子水平加剧，并表现出显著恶化的行为表型。为了确定依赖于LCN 2的整体炎症变化的程度，我们进行了RNAseq转录组学分析。与注射LPS的WT小鼠相比，注射LPS的Lcn 2 −/−小鼠具有独特的转录谱和显著升高的多种促炎分子水平。该分析揭示了几种LCN 2依赖性途径，包括细胞因子和趋化因子信号传导、核苷酸结合寡聚化结构域样受体信号传导和Janus激酶信号转导子和转录激活子信号传导。这些研究结果表明，LCN 2作为一个有效的保护因子在中枢神经系统中的全身炎症反应，并可能是一个潜在的候选限制败血症相关的中枢神经系统后遗症。
Sepsis is a prevalent health issue that can lead to central nervous system (CNS) inflammation with long-term behavioral and cognitive alterations. Using unbiased proteomic profiling of over 100 different cytokines, we found that Lipocalin-2 (LCN2) was the most substantially elevated protein in the CNS after peripheral administration of lipopolysaccharide (LPS). To determine whether the high level of LCN2 in the CNS is protective or deleterious, we challenged Lcn2−/− mice with peripheral LPS and determined effects on behavior and neuroinflammation. At a time corresponding to peak LCN2 induction in wild-type (WT) mice injected with LPS, Lcn2−/− mice challenged with LPS had exacerbated levels of pro-inflammatory cytokines and exhibited significantly worsened behavioral phenotypes. To determine the extent of global inflammatory changes dependent upon LCN2, we performed an RNAseq transcriptomic analysis. Compared with WT mice injected with LPS, Lcn2−/− mice injected with LPS had unique transcriptional profiles and significantly elevated levels of multiple pro-inflammatory molecules. Several LCN2-dependent pathways were revealed with this analysis including, cytokine and chemokine signaling, nucleotide-binding oligomerization domain-like receptor signaling and Janus kinase-signal transducer and activator of transcription signaling. These findings demonstrate that LCN2 serves as a potent protective factor in the CNS in response to systemic inflammation and may be a potential candidate for limiting sepsis-related CNS sequelae.
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