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The STAT3/SETDB2 axis dictates NF-κB-mediated inflammation in macrophages during wound repair. 在伤口修复过程中,STAT3/SETDB2 轴决定了巨噬细胞中 NF-κB 介导的炎症。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.179017
Kevin D Mangum, Aaron denDekker, Qinmengge Li, Lam C Tsoi, Amrita D Joshi, William J Melvin, Sonya J Wolf, Jadie Y Moon, Christopher O Audu, James Shadiow, Andrea T Obi, Rachael Wasikowski, Emily C Barrett, Tyler M Bauer, Kylie Boyer, Zara Ahmed, Frank M Davis, Johann Gudjonsson, Katherine A Gallagher

Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified that the histone methyltransferase SETDB2 in macrophages drives tissue repair by repressing NF-κB-mediated inflammation. Complementary ATAC-Seq and RNA-Seq of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NF-κB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages, yet paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NF-κB component, RELA, leading to increased RELA/NF-κB-mediated inflammatory gene expression. Furthermore, RNA-Seq in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally coregulate overlapping genes. Finally, in diabetic wound macrophages, STAT3 expression and STAT3/SETDB2 binding were increased. We have identified what we believe to be a novel STAT3/SETDB2 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.

组织损伤后巨噬细胞从炎症表型向修复表型的转变是由调控炎症基因表达的表观遗传酶控制的。我们之前发现巨噬细胞中的组蛋白甲基转移酶 SETDB2 通过抑制 NF-κB 介导的炎症来推动组织修复。对从骨髓细胞中缺乏 SETDB2 的小鼠体内分离出的伤口巨噬细胞进行 ATAC-Seq 和 RNA-Seq 的互补分析发现,SETDB2 通过抑制 NF-κB 依赖性基因启动子的染色质可及性来抑制炎症基因程序。我们发现,巨噬细胞中 SETDB2 的表达需要 STAT3,但矛盾的是,STAT3 也是 SETDB2 的结合伙伴,它通过抑制 SETDB2 与 NF-κB 成分 RELA 的相互作用来抑制 SETDB2 的活性,从而导致 RELA/NF-κB 介导的炎症基因表达增加。此外,对 STAT3 缺失小鼠伤口巨噬细胞的 RNA-Seq 研究也证实了这一点,并发现 STAT3 和 SETDB2 在转录上核心化了重叠基因。最后,在糖尿病伤口巨噬细胞中,STAT3 的表达和 STAT3/SETDB2 的结合都有所增加。我们发现了一种新的 STAT3/SETDB2 轴,我们认为它能在组织修复过程中调节巨噬细胞表型,并可能成为糖尿病伤口不愈合的重要治疗靶点。
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引用次数: 0
Impact of genetic factors on antioxidant rescue of maternal diabetes-associated congenital heart disease. 遗传因素对母体糖尿病相关先天性心脏病抗氧化救援的影响。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.183516
Talita Z Choudhury, Sarah C Greskovich, Holly B Girard, Anupama S Rao, Yogesh Budhathoki, Emily M Cameron, Sara Conroy, Deqiang Li, Ming-Tao Zhao, Vidu Garg

Congenital heart disease (CHD) affects ~1% of live births. Although genetic and environmental etiologic contributors have been identified, the majority of CHD lacks a definitive cause, suggesting the role of gene-environment interactions (GxE) in disease pathogenesis. Maternal diabetes mellitus (matDM) is among the most prevalent environmental risk factors for CHD. However, there is a substantial knowledge gap in understanding how matDM acts upon susceptible genetic backgrounds to increase disease expressivity. Previously, we reported a GxE between Notch1 haploinsufficiency and matDM leading to increased CHD penetrance. Here, we demonstrate a cell lineage specific effect of Notch1 haploinsufficiency in matDM-exposed embryos, implicating endothelial/endocardial derived tissues in the developing heart. We report impaired atrioventricular cushion morphogenesis in matDM exposed Notch1+/- animals and show a synergistic effect of NOTCH1 haploinsufficiency and oxidative stress in dysregulation of gene regulatory networks critical for endocardial cushion morphogenesis in vitro. Mitigation of matDM-associated oxidative stress via SOD1 overexpression did not rescue CHD in Notch1 haploinsufficient mice compared to wildtype littermates. Our results show the combinatorial interaction of matDM-associated oxidative stress and a genetic predisposition, Notch1 haploinsufficiency, on cardiac development, supporting a GxE model for CHD etiology and suggesting that antioxidant strategies maybe ineffective in genetically-susceptible individuals.

先天性心脏病(CHD)约占活产婴儿的 1%。虽然遗传和环境致病因素已被确定,但大多数先天性心脏病缺乏明确的病因,这表明基因与环境的相互作用(GxE)在疾病发病机制中起着重要作用。母体糖尿病(matDM)是导致先天性心脏病最普遍的环境风险因素之一。然而,在了解母体糖尿病如何作用于易感基因背景以增加疾病表现力方面还存在很大的知识差距。此前,我们报道了 Notch1 单倍体缺失和 matDM 之间的 GxE 导致 CHD 穿透性增加。在这里,我们证明了在暴露于 matDM 的胚胎中,Notch1 单倍体缺陷具有细胞系特异性效应,这与发育中心脏的内皮/心内膜衍生组织有关。我们报告了暴露于 matDM 的 Notch1+/- 动物的房室垫形态发生受损的情况,并显示了 NOTCH1 单倍体缺陷和氧化应激在体外对心内膜垫形态发生至关重要的基因调控网络失调的协同效应。与野生型小鼠相比,通过过量表达 SOD1 缓解 matDM 相关的氧化应激并不能挽救 Notch1 单倍体缺陷小鼠的 CHD。我们的研究结果表明,matDM相关氧化应激和遗传易感性(Notch1单倍体缺失)对心脏发育有联合作用,支持CHD病因的GxE模型,并表明抗氧化策略可能对遗传易感个体无效。
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引用次数: 0
Circulating proteins linked to apoptosis processes and fast development of end-stage kidney disease in diabetes. 与糖尿病患者细胞凋亡过程和终末期肾病快速发展有关的循环蛋白。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.178373
Katsuhito Ihara, Eiichiro Satake, Parker C Wilson, Bozena Krolewski, Hiroki Kobayashi, Zaipul I Md Dom, Joseph Ricca, Jonathan Wilson, Jonathan M Dreyfuss, Monika A Niewczas, Alessandro Doria, Robert G Nelson, Marcus G Pezzolesi, Benjamin D Humphreys, Kevin Duffin, Andrzej S Krolewski

Many circulating proteins are associated with risk of ESKD, but their source and the biological pathways/disease processes they represent are unclear. Using OLINK proteomics platform, concentrations of 455 proteins were measured in plasma specimens obtained at baseline from 399 individuals with diabetes. Elevated concentrations of 46 circulating proteins were associated (P < 1 × 10-5) with development of ESKD (n = 143) during 7-15 years of follow-up. Twenty of these proteins enriched apoptosis/TNF receptor signaling pathways. A subset of 20 proteins (5-7 proteins), summarized as an apoptosis score, together with clinical variables accurately predicted risk of ESKD. Expression of genes encoding the 46 proteins in peripheral WBCs showed no difference between cells from individuals who did or did not develop ESKD. In contrast, plasma concentration of many of the 46 proteins differed by this outcome. In single-nucleus RNA-Seq analysis of kidney biopsies, the majority of genes encoding for the 20 apoptosis/TNF receptor proteins were overexpressed in injured versus healthy proximal tubule cells. Expression of these 20 genes also correlated with the overall index of apoptosis in these cells. Elevated levels of circulating proteins flagging apoptotic processes/TNF receptor signaling pathways - and likely originating from kidney cells, including injured/apoptotic proximal tubular cells - preceded the development of ESKD.

许多循环蛋白与 ESKD 风险有关,但其来源及其代表的生物途径/疾病过程尚不清楚。利用 OLINK 蛋白质组学平台,测量了 399 名糖尿病患者基线血浆标本中 455 种蛋白质的浓度。在7-15年的随访期间,46种循环蛋白浓度的升高(P < 1 × 10-5)与ESKD(n = 143)的发展有关。其中 20 种蛋白质丰富了细胞凋亡/TNF 受体信号通路。20 个蛋白质的子集(5-7 个蛋白质)总结为细胞凋亡评分,与临床变量一起可准确预测 ESKD 的风险。外周白细胞中编码这 46 种蛋白质的基因的表达在罹患或未罹患 ESKD 的人的细胞中没有差异。相反,血浆中 46 种蛋白质中的许多蛋白质的浓度却因这一结果而不同。在对肾脏活检组织进行的单核 RNA-Seq 分析中,与健康的近端肾小管细胞相比,大多数编码 20 种凋亡/TNF 受体蛋白的基因在损伤的近端肾小管细胞中表达过高。这 20 个基因的表达还与这些细胞的整体凋亡指数相关。标志着凋亡过程/TNF 受体信号通路的循环蛋白水平升高--很可能来自肾脏细胞,包括受伤/凋亡的近端肾小管细胞--在 ESKD 发生之前就已存在。
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引用次数: 0
Development of a humanized mouse model with functional human materno-fetal interface immunity. 开发具有人类母胎界面免疫功能的人源化小鼠模型。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.176527
Shuai Dong, Cong Fu, Chang Shu, Min Xie, Yan Li, Jun Zou, Yi-Zi Meng, Peng Xu, Yan-Hong Shan, Hui-Min Tian, Jin He, Yong-Guang Yang, Zheng Hu

Materno-fetal immunity possesses specialized characteristics to ensure pathogen clearance while maintaining tolerance to the semiallogeneic fetus. Most of our understanding on human materno-fetal immunity is based on conventional rodent models that may not precisely represent human immunological processes owing to the huge evolutionary divergence. Herein, we developed a pregnant human immune system (HIS) mouse model through busulfan preconditioning, which hosts multilineage human immune subset reconstitution at the materno-fetal interface. Human materno-fetal immunity exhibits a tolerogenic feature at the midgestation stage (embryonic day [E] 14.5), and human immune regulatory subsets were detected in the decidua. However, the immune system switches to an inflammatory profile at the late gestation stage (E19). A cell-cell interaction network contributing to the alternations in the human materno-fetal immune atmosphere was revealed based on single-cell RNA-Seq analysis, wherein human macrophages played crucial roles by secreting several immune regulatory mediators. Furthermore, depletion of Treg cells at E2.5 and E5.5 resulted in severe inflammation and fetus rejection. Collectively, these results demonstrate that the pregnant HIS mouse model permits the development of functional human materno-fetal immunity and offers a tool for human materno-fetal immunity investigation to facilitate drug discovery for reproductive disorders.

母胎免疫具有特殊性,可确保清除病原体,同时保持对半同种胎儿的耐受性。我们对人类母胎免疫的认识大多基于传统的啮齿类动物模型,由于进化上的巨大差异,这些模型可能无法精确代表人类的免疫过程。在此,我们通过硫丹预处理建立了妊娠人类免疫系统(HIS)小鼠模型,该模型在母胎界面上承载了多线程人类免疫亚群重建。人类母胎免疫在妊娠中期(胚胎14.5天)表现出耐受性特征,在蜕膜中检测到人类免疫调节亚群。然而,免疫系统在妊娠晚期(E19)转为炎症特征。单细胞 RNA-Seq 分析揭示了导致人类母胎免疫氛围变化的细胞-细胞相互作用网络,其中人类巨噬细胞通过分泌多种免疫调节介质发挥了关键作用。此外,在E2.5和E5.5阶段消耗Treg细胞会导致严重的炎症和胎儿排斥反应。总之,这些结果表明,妊娠 HIS 小鼠模型允许开发功能性人类母胎免疫,并为人类母胎免疫研究提供了一种工具,有助于发现治疗生殖系统疾病的药物。
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引用次数: 0
Immune exhaustion in ME/CFS and long COVID. ME/CFS 和长期 COVID 中的免疫衰竭。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.183810
Natalie Eaton-Fitch, Penny Rudd, Teagan Er, Livia Hool, Lara Herrero, Sonya Marshall-Gradisnik

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are debilitating multisystemic conditions sharing similarities in immune dysregulation and cellular signaling pathways contributing to the pathophysiology. In this study, immune exhaustion gene expression was investigated in participants with ME/CFS or long COVID concurrently. RNA was extracted from peripheral blood mononuclear cells isolated from participants with ME/CFS (n = 14), participants with long COVID (n = 15), and healthy controls (n = 18). Participants with ME/CFS were included according to Canadian Consensus Criteria. Participants with long COVID were eligible according to the case definition for "Post COVID-19 Condition" published by the World Health Organization. RNA was analyzed using the NanoString nCounter Immune Exhaustion gene expression panel. Differential gene expression analysis in ME/CFS revealed downregulated IFN signaling and immunoglobulin genes, and this suggested a state of immune suppression. Pathway analysis implicated dysregulated macrophage activation, cytokine production, and immunodeficiency signaling. Long COVID samples exhibited dysregulated expression of genes regarding antigen presentation, cytokine signaling, and immune activation. Differentially expressed genes were associated with antigen presentation, B cell development, macrophage activation, and cytokine signaling. This investigation elucidates the intricate role of both adaptive and innate immune dysregulation underlying ME/CFS and long COVID, emphasizing the potential importance of immune exhaustion in disease progression.

肌痛性脑脊髓炎/慢性疲劳综合征(ME/CFS)和长期慢性疲劳综合征(long COVID)是使人衰弱的多系统疾病,它们在免疫失调和导致病理生理学的细胞信号通路方面有相似之处。本研究调查了同时患有 ME/CFS 和长焦虑症的参与者的免疫衰竭基因表达。从分离自 ME/CFS 患者(14 人)、长 COVID 患者(15 人)和健康对照组(18 人)的外周血单核细胞中提取 RNA。根据加拿大共识标准,患有 ME/CFS 的参与者被纳入研究范围。根据世界卫生组织发布的 "COVID-19后病症 "病例定义,长COVID患者符合条件。使用 NanoString nCounter Immune Exhaustion 基因表达面板分析 RNA。对 ME/CFS 的差异基因表达分析表明,IFN 信号和免疫球蛋白基因下调,这表明患者处于免疫抑制状态。通路分析显示巨噬细胞活化、细胞因子产生和免疫缺陷信号传导失调。长COVID样本中有关抗原递呈、细胞因子信号转导和免疫激活的基因表达失调。差异表达的基因与抗原呈递、B 细胞发育、巨噬细胞活化和细胞因子信号转导有关。这项研究阐明了适应性和先天性免疫失调在 ME/CFS 和长 COVID 中的复杂作用,强调了免疫衰竭在疾病进展中的潜在重要性。
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引用次数: 0
Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes. 雄激素产生、摄取和转化(APUC)基因决定了前列腺癌患者不同的临床结局。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.183158
Hannah E Bergom, Ella Boytim, Sean McSweeney, Negar Sadeghipour, Andrew Elliott, Rachel Passow, Eamon Toye, Xiuxiu Li, Pornlada Likasitwatanakul, Daniel M Geynisman, Scott M Dehm, Susan Halabi, Nima Sharifi, Emmanuel S Antonarakis, Charles J Ryan, Justin Hwang

BACKGROUNDProstate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADTs) are a cornerstone of treatment. ADT responsiveness may be associated with germline changes in genes that regulate androgen production, uptake, and conversion (APUC).METHODSWe analyzed whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx). We also interrogated the Caris Precision Oncology Alliance (POA) DNA (592-gene/whole exome) and RNA (whole transcriptome) next-generation sequencing databases. Algorithm for Linking Activity Networks (ALAN) was used to quantify all pairwise gene-to-gene associations. Real-world overall survival was determined from insurance claims data using Kaplan-Meier estimates.RESULTSSix APUC genes (HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1) exhibited coalescent gene behavior in a cohort of metastatic tumors (n = 208). In the Caris POA dataset, the 6 APUC genes (APUC-6) exhibited robust clustering in primary prostate (n = 4,490) and metastatic (n = 2,593) biopsies. Surprisingly, tumors with elevated APUC-6 expression had statically lower expression of AR, AR-V7, and AR signaling scores, suggesting ligand-driven disease biology. APUC-6 genes instead associated with the expression of alternative steroid hormone receptors, ESR1/2 and PGR. We used RNA expression of AR or APUC-6 genes to define 2 subgroups of tumors with differential association with hallmark pathways and cell surface targets.CONCLUSIONSThe APUC-6-high/AR-low tumors represented a subgroup of patients with good clinical outcomes, in contrast with the AR-high or neuroendocrine PCs. Altogether, measuring the aggregate expression of APUC-6 genes in current genomic tests identifies PCs that are ligand (rather than AR) driven and require distinct therapeutic strategies.FUNDINGNCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.

背景:前列腺癌(PC)由雄激素受体(AR)或其配体的异常信号驱动,雄激素剥夺疗法(ADT)是治疗的基础。ADT反应性可能与调节雄激素产生、摄取和转换(APUC)的基因的种系改变有关:我们分析了前列腺组织(SU2C/PCF、TCGA、GETx)的全外显子组测序(WES)和全转录组测序(WTS)数据。我们还查询了 Caris POA DNA(592 个基因/全外显子组)和 RNA(全转录组)NGS 数据库。连接活动网络算法(ALAN)用于量化所有基因对基因之间的配对关联。使用 Kaplan-Meier 估计法从保险理赔数据中确定真实世界的总生存期(OS):六个 APUC 基因(HSD3B1、HSD3B2、CYP3A43、CYP11A1、CYP11B1、CYP17A1)在一组转移性肿瘤(n = 208)中表现出基因凝聚行为。在 Caris POA 数据集中,6 个 APUC 基因(APUC-6)在原发性前列腺(n = 4,490 个)和转移性前列腺(n = 2,593 个)活检中表现出强大的聚类。令人惊讶的是,APUC-6表达量升高的肿瘤,其AR、AR-V7和AR信号转导评分的表达量呈静态降低趋势,这表明配体驱动的疾病生物学特性。APUC-6基因反而与替代类固醇激素受体ESR1/2和PGR的表达有关。我们利用AR或APUC-6基因的RNA表达来定义与标志性通路和细胞表面靶点有不同关联的两个肿瘤亚组:结论:APUC-6高/AR低肿瘤代表了临床预后良好的患者亚群,与AR高或神经内分泌性前列腺癌形成鲜明对比。总之,在目前的基因组测试中测量APUC-6基因的总表达量可以确定配体(而不是AR)驱动的PC,需要不同的治疗策略:NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.
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引用次数: 0
Neuronal SLC39A8 deficiency impairs cerebellar development by altering manganese homeostasis. 神经元 SLC39A8 缺乏会改变锰的平衡,从而损害小脑的发育。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.168440
Eun-Kyung Choi, Luisa Aring, Yujie Peng, Adele B Correia, Andrew P Lieberman, Shigeki Iwase, Young Ah Seo

Solute carrier family 39, member 8 (SLC39A8), is a transmembrane transporter that mediates the cellular uptake of zinc, iron, and manganese (Mn). Human genetic studies document the involvement of SLC39A8 in Mn homeostasis, brain development, and function. However, the role and pathophysiological mechanisms of SLC39A8 in the central nervous system remain elusive. We generated Slc39a8 neuron-specific knockout (Slc39a8-NSKO) mice to study SLC39A8 function in neurons. The Slc39a8-NSKO mice displayed markedly decreased Mn levels in the whole brain and brain regions, especially the cerebellum. Radiotracer studies using 54Mn revealed that Slc39a8-NSKO mice had impaired brain uptake of Mn. Slc39a8-NSKO cerebellums exhibited morphological defects and abnormal dendritic arborization of Purkinje cells. Reduced neurogenesis and increased apoptotic cell death occurred in the cerebellar external granular layer of Slc39a8-NSKO mice. Brain Mn deficiency in Slc39a8-NSKO mice was associated with motor dysfunction. Unbiased RNA-Seq analysis revealed downregulation of key pathways relevant to neurodevelopment and synaptic plasticity, including cAMP signaling pathway genes. We further demonstrated that Slc39a8 was required for the optimal transcriptional response to the cAMP-mediated signaling pathway. In summary, our study highlighted the essential roles of SLC39A8 in brain Mn uptake and cerebellum development and functions.

溶质运载家族 39 成员 8(SLC39A8)是一种跨膜转运体,可介导细胞对锌、铁和锰(Mn)的吸收。人类基因研究表明,SLC39A8 参与了锰的平衡、大脑发育和功能。然而,SLC39A8 在中枢神经系统中的作用和病理生理机制仍然难以捉摸。我们培育了 Slc39a8 神经元特异性基因敲除(Slc39a8-NSKO)小鼠来研究 SLC39A8 在神经元中的功能。Slc39a8-NSKO小鼠全脑和脑区(尤其是小脑)的锰含量明显下降。使用 54Mn 进行的放射性示踪剂研究显示,Slc39a8-NSKO 小鼠大脑对锰的吸收能力受损。Slc39a8-NSKO小鼠的小脑表现出形态缺陷和浦肯野细胞树突轴化异常。Slc39a8-NSKO小鼠小脑外颗粒层的神经发生减少,细胞凋亡增加。Slc39a8-NSKO小鼠的脑锰缺乏与运动功能障碍有关。无偏 RNA-Seq 分析显示,与神经发育和突触可塑性相关的关键通路(包括 cAMP 信号通路基因)出现下调。我们进一步证明,Slc39a8 是 cAMP 信号通路最佳转录反应所必需的。总之,我们的研究强调了SLC39A8在大脑锰吸收和小脑发育及功能中的重要作用。
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引用次数: 0
Parvalbumin interneuron impairment causes synaptic transmission deficits and seizures in SCN8A developmental and epileptic encephalopathy. 副突触中间神经元受损会导致 SCN8A 发育不良和癫痫性脑病的突触传递障碍和癫痫发作。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.181005
Raquel M Miralles, Alexis R Boscia, Shrinidhi Kittur, Jessica C Hanflink, Payal S Panchal, Matthew S Yorek, Tyler C J Deutsch, Caeley M Reever, Shreya R Vundela, Eric R Wengert, Manoj K Patel

SCN8A developmental and epileptic encephalopathy (DEE) is a severe epilepsy syndrome resulting from mutations in the voltage-gated sodium channel Nav1.6, encoded by the gene SCN8A. Nav1.6 is expressed in excitatory and inhibitory neurons, yet previous studies primarily focus on how SCN8A mutations affect excitatory neurons, with limited studies on the importance of inhibitory interneurons. Parvalbumin (PV) interneurons are a prominent inhibitory interneuron subtype that expresses Nav1.6. To assess PV interneuron function within SCN8A DEE, we used 2 mouse models harboring patient-derived SCN8A gain-of-function variants, Scn8aD/+, where the SCN8A variant N1768D is expressed globally, and Scn8aW/+-PV, where the SCN8A variant R1872W is selectively expressed in PV interneurons. Expression of the R1872W SCN8A variant selectively in PV interneurons led to development of spontaneous seizures and seizure-induced death. Electrophysiology studies showed that Scn8aD/+ and Scn8aW/+-PV interneurons were susceptible to depolarization block and exhibited increased persistent sodium current. Evaluation of synaptic connections between PV interneurons and pyramidal cells showed synaptic transmission deficits in Scn8aD/+ and Scn8aW/+-PV interneurons. Together, our findings indicate that PV interneuron failure via depolarization block along with inhibitory synaptic impairment likely elicits an overall inhibitory reduction in SCN8A DEE, leading to unchecked excitation and ultimately resulting in seizures and seizure-induced death.

SCN8A 发育性癫痫脑病(DEE)是一种严重的癫痫综合征,是由 SCN8A 基因编码的电压门控钠通道 Nav1.6 突变引起的。Nav1.6 在兴奋性和抑制性神经元中均有表达,但以往的研究主要集中于 SCN8A 突变如何影响兴奋性神经元,对抑制性中间神经元的重要性研究有限。为了在 SCN8A DEE 中评估 PV 中间神经元的功能,我们使用了 2 种携带源自患者的 SCN8A 功能增益变体的小鼠模型:Scn8aD/+ 和 Scn8aW/+-PV,前者的 SCN8A 变体 N1768D 全局表达,后者的 SCN8A 变体 R1872W 选择性地在 PV 中间神经元中表达。R1872W SCN8A变体选择性地在PV中间神经元中表达会导致自发性癫痫发作和癫痫发作诱导的死亡。电生理学研究表明,Scn8aD/+和Scn8aW/+-PV中间神经元易受去极化阻滞的影响,并表现出持续性钠电流增加。对PV中间神经元和锥体细胞之间的突触连接进行的评估显示,Scn8aD/+和Scn8aW/+-PV中间神经元存在突触传递缺陷。总之,我们的研究结果表明,通过去极化阻滞导致的 PV 中间神经元衰竭以及抑制性突触损伤可能会引起 SCN8A DEE 的整体抑制性降低,从而导致无节制的兴奋,并最终导致癫痫发作和癫痫发作诱导的死亡。
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引用次数: 0
Glymphatic influx and clearance are perturbed in Huntington's disease. 亨廷顿氏病的淋巴细胞流入和清除受到干扰。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.172286
Hongshuai Liu, Lin Chen, Chuangchuang Zhang, Chang Liu, Yuguo Li, Liam Cheng, Yuxiao Ouyang, Catherine Rutledge, John Anderson, Zhiliang Wei, Ziqin Zhang, Hanzhang Lu, Peter Cm van Zijl, Jeffrey J Iliff, Jiadi Xu, Wenzhen Duan

The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of Huntington's disease (HD). The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid and cerebrospinal fluid (CSF), supporting interstitial solute clearance of brain wastes. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure d-glucose clearance from CSF as a tool to predict glymphatic function in a mouse model of HD. We found significantly diminished CSF clearance efficiency in HD mice before phenotypic onset. The impairment of CSF clearance efficiency worsened with disease progression. These DGE MRI findings in compromised glymphatic function were further verified with fluorescence-based imaging of CSF tracer influx, suggesting an impaired glymphatic function in premanifest HD. Moreover, expression of the astroglial water channel aquaporin-4 in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain and human HD brain. Our data, acquired using a clinically translatable MRI, indicate a perturbed glymphatic network in the HD brain. Further validation of these findings in clinical studies will provide insights into the potential of glymphatic clearance as a therapeutic target as well as an early biomarker in HD.

突变亨廷汀蛋白聚集体在神经元中的积聚是亨廷顿氏病(HD)的病理特征。淋巴系统是一个全脑血管周围网络,可促进脑间质(ISF)和脑脊液(CSF)的交换,支持脑间质溶质清除脑废物。在这项研究中,我们采用动态葡萄糖增强(DGE)核磁共振成像技术测量脑脊液中 D-葡萄糖的清除率,以此来预测 HD 小鼠模型的血糖功能。我们发现,HD 小鼠在表型发病前的 CSF 清除率明显降低。随着病情的发展,CSF清除效率的损害会进一步恶化。基于荧光成像的脑脊液示踪剂流入进一步证实了DGE磁共振成像发现的甘液功能受损,这表明HD发病前的甘液功能受损。此外,在HD小鼠和人类HD大脑中,星形胶质细胞水通道aquaporin-4(AQP4)在血管周围的表达明显减少,而AQP4是血气功能的关键介质。我们使用可用于临床的核磁共振成像获得的数据表明,HD 大脑中的血糖网络受到了干扰。在临床研究中进一步验证这些发现将有助于深入了解甘液清除作为治疗目标和 HD 早期生物标志物的潜力。
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引用次数: 0
NK cell subsets define sustained remission in rheumatoid arthritis. NK 细胞亚群决定了类风湿性关节炎的持续缓解。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-17 DOI: 10.1172/jci.insight.182390
Carl Coyle, Margaret Ma, Yann Abraham, Christopher B Mahony, Kathryn Steel, Catherine Simpson, Nadia Guerra, Adam P Croft, Stephen Rapecki, Andrew Cope, Rowann Bowcutt, Esperanza Perucha

Rheumatoid Arthritis (RA) is an immune-mediated, chronic inflammatory condition. With modern therapeutics and evidence-based management strategies, achieving sustained remission is increasingly common. To prevent complications associated with prolonged use of immunosuppressants, drug tapering or withdrawal is recommended. However, due to the lack of tools that define immunological remission, disease flares are frequent, highlighting the need for a more precision medicine-based approach. Utilising high dimensional phenotyping platforms, we set out to define peripheral blood immunological signatures of sustained remission in RA. We identified that CD8+CD57+KIR2DL1+ NK cells are associated with sustained remission. Functional studies uncovered an NK cell subset characterized by normal degranulation responses and reduced pro-inflammatory cytokine expression, which was elevated in sustained remission. Furthermore, flow cytometric analysis of NK cells from synovial fluid combined with interrogation of a publicly available single cell RNA-seq dataset of synovial tissue from active RA identified a deficiency of the phenotypic characteristics associated with this NK cell remission signature. In summary, we have uncovered a novel RA remission signature associated with compositional changes in NK cell phenotype and function that has implications for understanding the impact of sustained remission on host immunity and distinct features which may define operational tolerance in RA.

类风湿性关节炎(RA)是一种免疫介导的慢性炎症。随着现代疗法和循证管理策略的发展,获得持续缓解的情况越来越普遍。为防止长期使用免疫抑制剂引起并发症,建议减药或停药。然而,由于缺乏界定免疫学缓解的工具,疾病复发的情况时有发生,这凸显了对基于精准医疗的方法的需求。利用高维表型平台,我们着手定义RA持续缓解的外周血免疫特征。我们发现 CD8+CD57+KIR2DL1+ NK 细胞与持续缓解相关。功能研究发现了一个以正常脱颗粒反应和促炎细胞因子表达减少为特征的NK细胞亚群,该亚群在持续缓解期升高。此外,我们对滑液中的 NK 细胞进行了流式细胞分析,并对公开的活动性 RA 滑膜组织单细胞 RNA-seq 数据集进行了分析,发现了与这种 NK 细胞缓解特征相关的表型特征的不足之处。总之,我们发现了一种新的 RA 缓解特征,它与 NK 细胞表型和功能的组成变化有关,有助于理解持续缓解对宿主免疫的影响,以及可能定义 RA 运行耐受性的独特特征。
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