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Aldosterone-induced salt appetite requires HSD2 neurons. 醛固酮诱导的盐食欲需要 HSD2 神经元。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-24 DOI: 10.1172/jci.insight.175087
Silvia Gasparini, Lila Peltekian, Miriam C McDonough, Chidera Ja Mitchell, Marco Hefti, Jon M Resch, Joel C Geerling

Excessive aldosterone production increases the risk of heart disease, stroke, dementia, and death. Aldosterone increases both sodium retention and sodium consumption, and increased sodium consumption may worsen end-organ damage in patients with aldosteronism. Preventing this increase could improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we previously identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its pre-receptor regulator, 11-beta-hydroxysteroid dehydrogenase 2 (HSD2). In the present study, we identified HSD2 neurons in the human brain, then used a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirmed that dietary sodium deprivation increases aldosterone production, salt intake, and HSD2 neuron activity. Next, we showed that continuous chemogenetic stimulation of HSD2 neurons causes a large and specific increase in salt intake. Finally, we use dose-response studies and genetically targeted ablation of HSD2 neurons to show that these neurons are necessary for aldosterone-induced salt intake. Identifying HSD2 neurons in the human brain and establishing their necessity for aldosterone-induced salt intake in mice improves our understanding of appetitive circuits and highlights this small cell population as a therapeutic target for moderating dietary sodium.

醛固酮分泌过多会增加罹患心脏病、中风、痴呆症和死亡的风险。醛固酮会增加钠潴留和钠消耗,钠消耗增加可能会加重醛固酮增多症患者的内脏损害。防止这种增加可改善预后,但醛固酮诱导钠食欲的行为机制仍不清楚。在啮齿类动物中,我们先前发现了对醛固酮敏感的神经元,它们表达矿质皮质激素受体及其前受体调节剂--11-beta-羟基类固醇脱氢酶 2(HSD2)。在本研究中,我们鉴定了人脑中的 HSD2 神经元,然后利用小鼠模型评估了它们在醛固酮诱导的盐摄入中的作用。首先,我们证实了饮食中钠的剥夺会增加醛固酮的产生、盐的摄入和 HSD2 神经元的活性。接着,我们证明了对 HSD2 神经元的持续化学刺激会导致盐摄入量的大幅和特异性增加。最后,我们利用剂量反应研究和基因靶向消减 HSD2 神经元的方法证明,这些神经元是醛固酮诱导盐摄入的必要条件。鉴定人脑中的 HSD2 神经元并确定它们对小鼠醛固酮诱导的盐摄入的必要性,增进了我们对食欲回路的了解,并突出了这一小细胞群作为调节膳食钠的治疗靶点的重要性。
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引用次数: 0
The contribution of neutrophils to bacteriophage clearance and pharmacokinetics in vivo. 中性粒细胞对体内噬菌体清除和药代动力学的贡献
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.181309
Arne Echterhof, Tejas Dharmaraj, Arya Khosravi, Robert McBride, Lynn Miesel, Ju-Hsin Chia, Patrick M Blankenberg, Kun-Yuan Lin, Chien-Chang Shen, Yu-Ling Lee, Yu-Chuan Yeh, Wei Ting Liao, Francis G Blankenberg, Krystyna Dąbrowska, Derek F Amanatullah, Adam R Frymoyer, Paul L Bollyky

With the increasing prevalence of antimicrobial-resistant bacterial infections, there is interest in using bacteriophages (phages) to treat such infections. However, the factors that govern bacteriophage pharmacokinetics in vivo remain poorly understood. Here, we have examined the contribution of neutrophils, the most abundant phagocytes in the body, to the pharmacokinetics of i.v. administered bacteriophage in uninfected mice. A single dose of LPS-5, a bacteriophage recently used in human clinical trials to treat drug-resistant Pseudomonas aeruginosa, was administered i.v. to both immunocompetent BALB/c and neutropenic CD1 mice. Phage concentrations were assessed in peripheral blood and spleen at 0.25, 1, 2, 4, 8, 12, and 24 hours after administration by plaque assay and qPCR. We observed that the phage clearance was only minimally affected by neutropenia. Indeed, the half-lives of phages in blood in BALB/c and CD1 mice were 3.45 and 3.66 hours, respectively. These data suggest that neutrophil-mediated phagocytosis is not a major determinant of phage clearance. Conversely, we observed a substantial discrepancy in circulating phage levels over time when measured by qPCR versus plaque assay, suggesting that significant inactivation of circulating phages occurs over time. These data indicate that alternative factors, but not neutrophils, inactivate i.v. administered phages.

随着耐抗菌细菌感染的日益流行,人们对使用噬菌体(噬菌体)治疗此类感染产生了兴趣。然而,人们对影响噬菌体体内药代动力学的因素仍然知之甚少。在这里,我们研究了嗜中性粒细胞(人体内数量最多的吞噬细胞)对未感染小鼠静脉注射噬菌体药代动力学的影响。对免疫功能正常的 BALB/c 小鼠和中性粒细胞增多的 CD1 小鼠静脉注射单剂量 LPS-5,这是一种最近用于人类临床试验治疗耐药铜绿假单胞菌的噬菌体。在给药后 0.25、1、2、4、8、12 和 24 小时,通过斑块检测和 qPCR 评估外周血和脾脏中的噬菌体浓度。我们观察到,噬菌体清除率受中性粒细胞减少症的影响很小。事实上,噬菌体在 BALB/c 和 CD1 小鼠血液中的半衰期分别为 3.45 和 3.66 小时。这些数据表明,中性粒细胞介导的吞噬作用并不是噬菌体清除的主要决定因素。相反,我们观察到通过 qPCR 与斑块检测法测量的循环噬菌体水平随着时间的推移存在很大差异,这表明循环噬菌体会随着时间的推移发生显著失活。这些数据表明,替代因子而非中性粒细胞会使静脉注射的噬菌体失活。
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引用次数: 0
Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation. 迁移性 CD103+ 树突状细胞的后天免疫刺激表型会促进角膜移植后的异体免疫。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.182469
Tomás Blanco, Hayate Nakagawa, Aytan Musayeva, Mark Krauthammer, Rohan Bir Singh, Akitomo Narimatsu, Hongyan Ge, Sara I Shoushtari, Reza Dana

After transplantation, Th1-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ DCs (DC2) and CD103+ DCs (DC1). This interaction necessitates further investigation in the context of transplant immunity. We used well-established preclinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+ DC1 demonstrate a tolerogenic phenotype that modulates the immunogenic capacity of CD11b+ DC2 primarily mediated by IL-10, suppressing alloreactive CD4+ Th1 cells via the PD-L1/PD-1 pathway and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGF-β1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+ Th1 cells induced migratory CD103+ DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers, including αvβ8 integrin and IL-10, and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex vivo induced tolerogenic CD103+ DC1 (iDC1) effectively inhibited Th1 polarization and preserved the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+ DC1 in modulating host alloimmune responses.

移植后,T辅助细胞1(Th1)介导的免疫排斥是移植失败的主要原因。Th1细胞的致敏作用是通过抗原递呈细胞亚群,特别是CD11b+树突状细胞(DC2)和CD103+树突状细胞(DC1)之间复杂且依赖环境的相互作用而发生的。这种相互作用需要在移植免疫的背景下进一步研究。我们利用成熟的角膜移植临床前模型,确定了迁移性 CD103+ DC1 在影响移植组织结果方面的不同作用。在未发炎角膜床的受者中,迁移性 CD103+DC1 表现出耐受表型,主要通过 IL-10 调节 CD11b+DC2 的免疫原性,通过 PD-L1/PD-1 途径抑制异性反应的 CD4+Th1 细胞,通过 αvβ8 整合素激活的 TGFβ1 增强 Treg 介导的耐受性,从而促进移植物存活。相反,在角膜床有炎症和血管的受体中,CD4+Th1 细胞产生的 IFN-γ 会诱导 CD103+DC1 迁移,使其采用免疫刺激表型,其特点是下调包括 αvβ8 整合素和 IL-10 在内的调节标记物,上调 IL-12 和成本刺激分子 CD80/86,从而导致移植物失败。体内外诱导的耐受性 CD103+DC1(iDC1)的收养性转移能有效抑制 Th1 极化,并保留其生理对应物的耐受性表型。总之,我们的研究结果强调了 CD103+DC1 在调节宿主同种免疫反应中的重要作用。
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引用次数: 0
Epstein-Barr virus infection induces tissue-resident memory T cells in mucosal lymphoid tissues. Epstein Barr 病毒感染会诱导粘膜淋巴组织中的组织驻留记忆 T 细胞。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.173489
Daniel Kirchmeier, Yun Deng, Lisa Rieble, Michelle Böni, Fabienne Läderach, Patrick Schuhmachers, Alma Delia Valencia-Camargo, Anita Murer, Nicole Caduff, Bithi Chatterjee, Obinna Chijioke, Kyra Zens, Christian Münz

EBV contributes to around 2% of all tumors worldwide. Simultaneously, more than 90% of healthy human adults persistently carry EBV without clinical symptoms. In most EBV carriers, it is thought that virus-induced tumorigenesis is prevented by cell-mediated immunity. Specifically, memory CD8+ T cells recognize EBV-infected cells during latent and lytic infection. Using a symptomatic primary infection model, similar to infectious mononucleosis (IM), we found EBV-induced CD8+ tissue resident memory T cells (TRMs) in mice with a humanized immune system. These human TRMs were preferentially established after intranasal EBV infection in nasal-associated lymphoid tissues (NALT), equivalent to tonsils, the primary site of EBV infection in humans. They expressed canonical TRM markers, including CD69, CD103, and BLIMP-1, as well as granzyme B, CD107a, and CCL5. Despite cytotoxic activity and cytokine production ex vivo, these TRMs demonstrated reduced CD27 expression and proliferation and failed to control EBV viral loads in the NALT during infection, although effector memory T cells (TEMs) controlled viral titers in spleen and blood. Overall, TRMs are established in mucosal lymphoid tissues by EBV infection, but primarily, systemic CD8+ T cell expansion seems to control viral loads in the context of IM-like infection.

全球约有 2% 的肿瘤是由 Epstein Barr 病毒(EBV)引起的。同时,超过 90% 的健康成年人持续携带 EBV,但没有临床症状。在大多数 EBV 携带者中,人们认为病毒诱导的肿瘤发生是由细胞介导的免疫所阻止的。具体来说,记忆性 CD8+ T 细胞能在潜伏感染和溶解感染期间识别 EBV 感染细胞。通过使用类似于传染性单核细胞增多症(IM)的无症状原发感染模型,我们在具有人源化免疫系统的小鼠体内发现了 EBV 诱导的 CD8+ 组织驻留记忆 T 细胞(TRMs)。鼻腔相关淋巴组织(NALT)相当于扁桃体,是人类感染 EBV 的主要部位。它们表达典型的 TRM 标记,包括 CD69、CD103 和 BLIMP-1,以及 Granzyme B、CD107a 和 CCL5。尽管这些TRMs在体外具有细胞毒性活性并能产生细胞因子,但它们的CD27表达和增殖能力都有所下降,在感染期间也未能控制NALT中的EBV病毒载量,尽管效应记忆T细胞(TEMs)能控制脾脏和血液中的病毒滴度。总之,EBV 感染会在粘膜淋巴组织中建立 TRMs,但在类似 IM 感染的情况下,似乎主要是全身 CD8+ T 细胞扩增能控制病毒载量。
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引用次数: 0
Progesterone promotes CXCl2-dependent vaginal neutrophil killing by activating cervical resident macrophage-neutrophil crosstalk. 黄体酮通过激活宫颈驻留巨噬细胞与中性粒细胞之间的串联作用,促进依赖 Cxcl2 的阴道中性粒细胞杀伤作用。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.177899
Carla Gómez-Oro, Maria C Latorre, Patricia Arribas-Poza, Alexandra Ibáñez-Escribano, Katia R Baca-Cornejo, Jorge Gallego-Valle, Natalia López-Escobar, Mabel Mondéjar-Palencia, Marjorie Pion, Luis A López-Fernández, Enrique Mercader, Federico Pérez-Milán, Miguel Relloso

Vaginal infections in women of reproductive age represent a clinical dilemma with significant socioeconomic implications. The current understanding of mucosal immunity failure during early pathogenic invasions that allows the pathogen to grow and thrive is far from complete. Neutrophils infiltrate most tissues following circadian patterns as part of normal repair, regulation of microbiota, or immune surveillance and become more numerous after infection. Neutrophils are responsible for maintaining vaginal immunity. Specific to the vagina, neutrophils continuously infiltrate at high levels, although during ovulation, they retreat to avoid sperm damage and permit reproduction. Here we show that, after ovulation, progesterone promotes resident vaginal macrophage-neutrophil crosstalk by upregulating Yolk sac early fetal organs (FOLR2+) macrophage CXCl2 expression, in a TNFA-patrolling monocyte-derived macrophage-mediated (CX3CR1hiMHCIIhi-mediated) manner, to activate the neutrophils' capacity to eliminate sex-transmitted and opportunistic microorganisms. Indeed, progesterone plays an essential role in conciliating the balance between the commensal microbiota, sperm, and the threat of pathogens because progesterone not only promotes a flurry of neutrophils but also increases neutrophilic fury to restore immunity after ovulation to thwart pathogenic invasion after intercourse. Therefore, modest progesterone dysregulations could lead to a suboptimal neutrophilic response, resulting in insufficient mucosal defense and recurrent unresolved infections.

育龄妇女的阴道感染是一个对社会经济有重大影响的临床难题。人们对早期病原体入侵时粘膜免疫失效,导致病原体生长和繁殖的认识还远远不够。作为正常修复、微生物群调节或免疫监视的一部分,中性粒细胞按照昼夜节律浸润大多数组织,并在感染后变得更多。中性粒细胞负责维持阴道免疫。在阴道中,中性粒细胞持续高水平浸润,但在排卵期间,它们会退缩以避免精子受损,并允许生殖。在这里,我们发现在排卵后,孕酮通过上调卵黄囊和胎儿早期器官(Folr2+(叶酸受体 2))巨噬细胞 Cxcl2 的表达,以 Tnfa-单核细胞源性巨噬细胞(Cx3cr1hi MHCIIhi)介导的方式,促进常驻阴道巨噬细胞-中性粒细胞的串联,从而激活中性粒细胞消除性传播和机会性微生物的能力。事实上,黄体酮在协调共生微生物群、精子和病原体威胁之间的平衡方面起着至关重要的作用:因为黄体酮不仅能促进中性粒细胞的大量繁殖,还能增加中性粒细胞的愤怒,从而在排卵后恢复免疫力,挫败性交后的病原体入侵。因此,适度的孕酮失调可能会导致中性粒细胞反应不理想,从而导致粘膜防御不足和反复感染。
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引用次数: 0
Antibody levels versus vaccination status in the outcome of older adults with COVID-19. 感染 COVID-19 的老年人的抗体水平与疫苗接种情况的关系。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.183913
Sylvia Mink, Christoph H Saely, Andreas Leiherer, Patrick Reimann, Matthias Frick, Janne Cadamuro, Wolfgang Hitzl, Heinz Drexel, Peter Fraunberger

BACKGROUNDDespite the currently prevailing, milder Omicron variant of COVID-19, older adults remain at elevated risk of hospital admission, critical illness, and death. Loss of efficacy of the immune system, including reduced strength, quality, and durability of antibody responses, may render generalized recommendations on booster vaccinations inadequate. There is a lack of data on the efficacy of antibody levels in older adults and on the utility of vaccination status versus antibody levels as a correlate of protection. It is further unclear whether antibody levels may be used to guide the timing of booster vaccinations in older adults.METHODSWe conducted a prospective multicenter cohort study comprising hospitalized patients with COVID-19. Anti-SARS-CoV-2 spike antibodies were measured on hospital admission. The primary endpoint was in-hospital mortality. Patients were stratified by age, antibody levels, and vaccination status. Multiple logistic regression and Cox regression analyses were conducted.RESULTSIn total, 785 older patients (≥60 years of age [a]) and 367 controls (<60a) were included. After adjusting for confounders, risk of mortality, ICU admission, endotracheal intubation, and oxygen administration was 4.9, 2.6, 6.5, and 2.3 times higher, respectively, if antibody levels were < 1,200 BAU/mL (aOR, 4.92 [95%CI, 2.59-9.34], P < 0.0001; aOR, 2.64 [95%CI, 1.52-4.62], P = 0.0006; aOR, 6.50 [95%CI, 1.48-28.47], P = 0.013; aOR, 2.34 [95%CI, 1.60-3.343], P < 0.0001). Older adults infected with the Omicron variant were approximately 6 times more likely to die if antibody levels were < 1,200 BAU/mL (aOR, 6.3 [95% CI, 2.43-16.40], P = 0.0002).CONCLUSIONAntibody levels were a stronger predictor of in-hospital mortality than vaccination status. Monitoring antibody levels may constitute a better and more direct approach for safeguarding older adults from adverse COVID-19 outcomes.

背景尽管目前流行较温和的 COVID-19 Omicron 变体,但老年人入院、危重病和死亡的风险仍然很高。免疫系统功效的丧失,包括抗体反应强度、质量和持久性的降低,可能会使关于加强接种疫苗的普遍建议变得不充分。关于抗体水平在老年人中的有效性,以及疫苗接种情况与抗体水平作为保护的相关因素之间的效用,目前还缺乏数据。我们进行了一项前瞻性多中心队列研究,研究对象包括 COVID-19 的住院患者。入院时测定了抗 SARS-CoV-2 尖峰抗体。主要终点是院内死亡率。根据年龄、抗体水平和疫苗接种情况对患者进行分层。结果共有 785 名老年患者(年龄≥60 岁 [a])和 367 名对照组患者(年龄≥60 岁 [b])。
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引用次数: 0
CXCL9, CXCL10, and CCL19 synergistically recruit T lymphocytes to skin in lichen planus. CXCL9、CXCL10 和 CCL19 在扁平苔藓患者的皮肤上协同招募 T 淋巴细胞。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.179899
Anna E Kersh, Satish Sati, Jianhe Huang, Christina Murphy, Olivia Ahart, Thomas H Leung

Lichen planus (LP) is a chronic, debilitating, inflammatory disease of the skin and mucous membranes that affects 1%-2% of Americans. Its molecular pathogenesis remains poorly understood, and there are no FDA-approved treatments. We performed single-cell RNA sequencing on paired blood and skin samples (lesional and nonlesional tissue) from 7 patients with LP. We discovered that LP keratinocytes and fibroblasts specifically secrete a combination of CXCL9, CXCL10, and CCL19 cytokines. Using an in vitro migration assay with primary human T cells, we demonstrated that CCL19 in combination with either of the other 2 cytokines synergistically enhanced recruitment of CD8+ T cells more than any individual cytokine. Moreover, exhausted T cells in lesional LP skin secreted CXCL13, which, along with CCL19, also enhanced recruitment of T cells, suggesting a feed-forward loop in LP. Finally, LP blood revealed decreased circulating naive CD8+ T cells compared with that in healthy volunteers, consistent with recruitment to skin. Molecular analysis of LP skin and blood samples increased our understanding of disease pathogenesis and identified CCL19 as a new therapeutic target for treatment.

扁平苔藓(LP)是一种慢性、使人衰弱的皮肤和粘膜炎症性疾病,1% 到 2% 的美国人患有此病。人们对这种疾病的分子发病机制仍然知之甚少,而且目前还没有获得美国食品及药物管理局批准的治疗方法。我们对 7 名 LP 患者的配对血液和皮肤样本(病变组织和非病变组织)进行了单细胞 RNA 测序。我们发现 LP 角质细胞和成纤维细胞会特异性分泌 CXCL9、CXCL10 和 CCL19 细胞因子。通过使用原代人类 T 细胞进行体外迁移试验,我们发现 CCL19 与其中任何一种细胞因子结合使用,都能协同增强 CD8 T 细胞的募集,其效果超过单个细胞因子的总和。此外,LP 病变皮肤中衰竭的 T 细胞会分泌 CXCL13,而 CXCL13 与 CCL19 也会增强 T 细胞的募集,这表明在 LP 中存在一个前馈循环。最后,与健康志愿者相比,LP患者的血液显示循环中的幼稚CD8 T细胞减少,这与皮肤的招募一致。对 LP 皮肤和血液样本的分子分析增加了我们对疾病发病机制的了解,并确定 CCL19 为新的治疗靶点。
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引用次数: 0
Autosomal dominant macular dystrophy linked to a chromosome 17 tandem duplication. 常染色体显性黄斑营养不良症与 17 号染色体串联重复有关。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-22 DOI: 10.1172/jci.insight.178768
Rabiat Adele, Rowaida Hussein, Erika Tavares, Kashif Ahmed, Matteo Di Scipio, Jason Charish, Minggao Liang, Simon Monis, Anupreet Tumber, Xiaoyan Chen, Tara A Paton, Nicole M Roslin, Christabel Eileen, Evgueni Ivakine, Nishanth E Sunny, Michael D Wilson, Eric Campos, Raju Vs Rajala, Jason T Maynes, Philippe P Monnier, Andrew D Paterson, Elise Héon, Ajoy Vincent

Hereditary Macular Dystrophies (HMDs) are a genetically diverse group of disorders that cause central vision loss due to photoreceptor and retinal pigment epithelium (RPE) damage. We investigated a family with a presumed novel autosomal dominant HMD characterized by faint, hypopigmented RPE changes involving the central retina. Genome and RNA sequencing identified the disease-causing variant to be a 560 kilobase tandem duplication on chromosome 17 [NC_000017.10 (hg19): g.4012590_4573014dup], which led to the formation of a novel ZZEF1-ALOX15 fusion gene, that upregulates ALOX15. ALOX15 encodes a lipoxygenase involved in polyunsaturated fatty acid metabolism. Functional studies showed retinal disorganization, and photoreceptor and RPE damage following electroporation of the chimera transcript in mouse retina. Photoreceptor damage also occurred following electroporation with a native ALOX15 transcript but not with a near-null ALOX15 transcript. Affected patients' lymphoblasts demonstrated lower levels of ALOX15 substrates and an accumulation of neutral lipids. We implicated the fusion gene as the cause of this family's HMD, due to mis-localization and overexpression of ALOX15, driven by the ZZEF1 promoter. To our knowledge, this is the first reported instance of a fusion gene leading to HMD or inherited retinal dystrophy, highlighting the need to prioritize duplication analysis in unsolved retinal dystrophies.

遗传性黄斑营养不良症(HMDs)是一组遗传多样性的疾病,由于感光器和视网膜色素上皮(RPE)受损而导致中心视力丧失。我们对一个家族进行了调查,这个家族患有一种假定的新型常染色体显性 HMD,其特征是视网膜中央出现模糊、色素减退的 RPE 变化。基因组和 RNA 测序确定了致病变体是 17 号染色体上一个 560 千碱基的串联重复[NC_000017.10 (hg19):g.4012590_4573014dup],它导致了一个新型 ZZEF1-ALOX15 融合基因的形成,该基因能上调 ALOX15。ALOX15 编码一种参与多不饱和脂肪酸代谢的脂氧合酶。功能研究显示,在小鼠视网膜中电穿孔嵌合转录本后,视网膜会出现紊乱,感光器和 RPE 会受损。电穿孔原生 ALOX15 转录本也会造成感光器损伤,但 ALOX15 转录本近乎缺失时则不会。受影响患者的淋巴母细胞表现出较低水平的 ALOX15 底物和中性脂质积累。我们认为该融合基因是导致该家族出现 HMD 的原因,因为 ALOX15 在 ZZEF1 启动子的驱动下发生了错误定位和过度表达。据我们所知,这是首次报道融合基因导致HMD或遗传性视网膜营养不良症的病例,这突出表明有必要优先对尚未解决的视网膜营养不良症进行重复分析。
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引用次数: 0
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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