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Identification of RTS,S/AS01 vaccine-induced humoral biomarkers predictive of protection against controlled human malaria infection. 鉴定 RTS,S/AS01 疫苗诱导的体液生物标志物,预测受控人类疟疾感染的保护作用。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-08 DOI: 10.1172/jci.insight.178801
Rachel L Spreng, Kelly E Seaton, Lin Lin, Sir'Tauria Hilliard, Gillian Q Horn, Milite Abraha, Aaron W Deal, Kan Li, Alexander J Carnacchi, Elizabeth Feeney, Siam Shabbir, Lu Zhang, Valerie Bekker, Sarah V Mudrak, Sheetij Dutta, Laina D Mercer, Scott Gregory, C Richter King, Ulrike Wille-Reece, Erik Jongert, Neville K Kisalu, Georgia D Tomaras, S Moses Dennison

BACKGROUNDThe mechanism(s) responsible for the efficacy of WHO-recommended malaria vaccine RTS,S/AS01 are not completely understood. We previously identified RTS,S vaccine-induced Plasmodium falciparum circumsporozoite protein-specific (PfCSP-specific) antibody measures associated with protection from controlled human malaria infection (CHMI). Here, we tested the protection-predicting capability of these measures in independent CHMI studies.METHODSVaccine-induced total serum antibody (immunoglobulins, Igs) and subclass antibody (IgG1 and IgG3) responses were measured by biolayer interferometry and the binding antibody multiplex assay, respectively. Immune responses were compared between protected and nonprotected vaccinees using univariate and multivariate logistic regression.RESULTSBlinded prediction analysis showed that 5 antibody binding measures, including magnitude-avidity composite of serum Ig specific for PfCSP, major NANP repeats and N-terminal junction, and PfCSP- and NANP-specific IgG1 subclass magnitude, had good prediction accuracy (area under the receiver operating characteristic curves [ROC AUC] > 0.7) in at least 1 trial. Furthermore, univariate analysis showed a significant association between these antibody measures and protection (odds ratios 2.6-3.1). Multivariate modeling of combined data from 3 RTS,S CHMI trials identified the combination of IgG1 NANP binding magnitude plus serum NANP and N-junction Ig binding magnitude-avidity composite as the best predictor of protection (95% confidence interval for ROC AUC 0.693-0.834).CONCLUSIONThese results reinforce our previous findings and provide a tool for predicting protection in future trials.TRIAL REGISTRATIONClinicalTrials.gov NCT03162614, NCT03824236, NCT01366534, and NCT01857869.FUNDINGThis study was supported by Bill & Melinda Gates Foundation's Global Health-Discovery Collaboratory grants (INV-008612 and INV-043419) to GDT.

背景世界卫生组织推荐的疟疾疫苗RTS,S/AS01的药效机制尚未完全明了。我们曾发现 RTS,S 疫苗诱导的恶性疟原虫圆孢子虫蛋白特异性(PfCSP-specific)抗体与人类疟疾控制感染(CHMI)保护相关。方法疫苗诱导的血清总抗体(免疫球蛋白,Igs)和亚类抗体(IgG1 和 IgG3)反应分别通过生物层干涉测量法和结合抗体多重测定法进行测量。结果盲预测分析表明,在至少一项试验中,5种抗体结合度量,包括针对PfCSP、主要NANP重复序列和N端连接的血清特异性Ig的大小-活力复合值,以及PfCSP和NANP特异性IgG1亚类的大小,具有良好的预测准确性(接收器操作特征曲线下面积 [ROC AUC] > 0.7)。此外,单变量分析表明,这些抗体指标与保护之间存在显著关联(几率比 2.6-3.1)。对 3 项 RTS,S CHMI 试验的综合数据进行多变量建模后发现,IgG1 NANP 结合力大小加上血清 NANP 和 N 结 Ig 结合力大小-湿度复合值是预测保护作用的最佳指标(ROC AUC 的 95% 置信区间为 0.693-0.834)。结论这些结果加强了我们之前的研究结果,并为在未来的试验中预测保护提供了一种工具。试验注册ClinicalTrials.gov NCT03162614、NCT03824236、NCT01366534 和 NCT01857869.FUNDING 本研究得到了比尔及梅琳达-盖茨基金会全球健康发现合作基金(INV-008612 和 INV-043419)对 GDT 的资助。
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引用次数: 0
Systemic gene therapy corrects the neurological phenotype in a mouse model of NGLY1 deficiency. 全身基因疗法可纠正 NGLY1 缺乏症小鼠模型的神经表型。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-08 DOI: 10.1172/jci.insight.183189
Ailing Du, Kun Yang, Xuntao Zhou, Lingzhi Ren, Nan Liu, Chen Zhou, Jialing Liang, Nan Yan, Guangping Gao, Dan Wang

The cytoplasmic peptide:N-glycanase (NGLY1) is ubiquitously expressed and functions as a de-N-glycosylating enzyme that degrades misfolded N-glycosylated proteins. NGLY1 deficiency due to biallelic loss-of-function NGLY1 variants is an ultrarare autosomal recessive deglycosylation disorder with multisystemic involvement; the neurological manifestations represent the main disease burden. Currently, there is no treatment for this disease. To develop a gene therapy, we first characterized a tamoxifen-inducible Ngly1-knockout (iNgly1) C57BL/6J mouse model, which exhibited symptoms recapitulating human disease, including elevation of the biomarker GlcNAc-Asn, motor deficits, kyphosis, Purkinje cell loss, and gait abnormalities. We packaged a codon-optimized human NGLY1 transgene cassette into 2 adeno-associated virus (AAV) capsids, AAV9 and AAV.PHPeB. Systemic administration of the AAV.PHPeB vector to symptomatic iNgly1 mice corrected multiple disease features at 8 weeks after treatment. Furthermore, another cohort of AAV.PHPeB-treated iNgly1 mice were monitored over a year and showed near-complete normalization of the neurological aspects of the disease phenotype, demonstrating the durability of gene therapy. Our data suggested that brain-directed NGLY1 gene replacement via systemic delivery is a promising therapeutic strategy for NGLY1 deficiency. Although the superior CNS tropism of AAV.PHPeB vector does not translate to primates, emerging AAV capsids with enhanced primate CNS tropism will enable future translational studies.

细胞质肽:N-糖化酶(NGLY1)普遍表达,是一种去 N-糖基化酶,可降解折叠错误的 N-糖基化蛋白质。NGLY1双倍功能缺失变体导致的NGLY1缺乏症是一种多系统受累的超常染色体隐性去N-糖基化疾病;神经系统表现是该病的主要疾病负担。目前,这种疾病还没有治疗方法。为了开发基因疗法,我们首先鉴定了一种他莫昔芬诱导的 Ngly1 基因敲除(iNgly1)C57BL/6J 小鼠模型,该模型表现出与人类疾病相似的症状,包括生物标志物 GlcNAc-Asn (GNA)升高、运动障碍、脊柱后凸、浦肯野细胞缺失和步态异常。我们将经过密码子优化的人类 NGLY1 转基因盒打包到两种腺相关病毒(AAV)包壳中,即 AAV9 和 AAV.PHPeB。对有症状的 iNgly1 小鼠全身施用 AAV.PHPeB 载体可在治疗后八周纠正多种疾病特征。此外,我们还对另一组接受过 AAV.PHPeB 治疗的 iNgly1 小鼠进行了长达一年的监测,结果显示疾病表型的神经方面几乎完全正常化,这证明了基因疗法的持久性。我们的数据表明,通过全身给药进行脑定向 NGLY1 基因替代是一种治疗 NGLY1 缺乏症的有效策略。虽然AAV.PHPeB载体对中枢神经系统的特异性并不能转化到灵长类动物身上,但新出现的具有增强灵长类动物中枢神经系统特异性的AAV囊壳将使未来的转化研究成为可能。
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引用次数: 0
Hidden hearing loss in a Charcot-Marie-Tooth type 1A mouse model. 夏科-玛丽-牙1A型小鼠模型中的隐性听力损失
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-08 DOI: 10.1172/jci.insight.180315
Luis R Cassinotti, Lingchao Ji, M Caroline Yuk, Aditi S Desai, Nathan D Cass, Zahara A Amir, Gabriel Corfas

Hidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound-evoked cochlear compound action potentials, has been proposed to contribute to hearing difficulty in noisy environments in people with normal hearing thresholds and has become a widespread complaint. While most studies on HHL pathogenesis have focused on inner hair cell (IHC) synaptopathy, we recently showed that transient auditory nerve (AN) demyelination also causes HHL in mice. To test the effect of myelinopathy on hearing in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibited the functional hallmarks of HHL together with disorganization of AN heminodes near the IHCs with minor loss of AN fibers. These results support the hypothesis that mild disruptions of AN myelination can cause HHL and that heminodal defects contribute to the alterations in the sound-evoked cochlear compound action potentials seen in this mouse model. Furthermore, these findings suggest that patients with CMT1A or other mild peripheral neuropathies are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in patients with CMT1A might help develop robust clinical tests for HHL, which are currently lacking.

隐性听力损失(HHL)是最近描述的一种听觉神经病变,其特点是听阈正常,但声音诱发的耳蜗复合动作电位降低。虽然大多数关于HHL发病机制的研究都集中于内毛细胞(IHC)突触病,但我们最近发现,短暂性听神经(AN)脱髓鞘也会导致小鼠HHL。为了测试髓鞘病变在临床相关模型中对听力的影响,我们研究了夏科-玛丽-牙1A型(CMT1A)小鼠模型,这是人类最常见的遗传性周围神经病。CMT1A 小鼠表现出 HHL 的功能特征,以及 IHC 附近 AN heminodes 的紊乱和 AN 纤维的轻微缺失。这些结果支持了这样的假设,即轻微的AN髓鞘化破坏可导致HHL,而heminodal缺陷可导致该小鼠模型中出现的声诱发耳蜗复合动作电位的改变。这些发现还表明,CMT1A 或其他轻度周围神经病患者很可能患有 HHL。此外,这些结果还表明,对 CMT1A 患者听力的研究可能有助于开发出目前尚缺乏的针对 HHL 的可靠临床测试。
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引用次数: 0
Aldehyde dehydrogenase 2 preserves kidney function by countering acrolein-induced metabolic and mitochondrial dysfunction. 醛脱氢酶 2 通过对抗丙烯醛引起的代谢和线粒体功能障碍来保护肾功能。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-08 DOI: 10.1172/jci.insight.179871
Szu-Yuan Li, Ming-Tsun Tsai, Yu-Ming Kuo, Hui-Min Yang, Zhen-Jie Tong, Hsiao-Wei Cheng, Chih-Ching Lin, Hsiang-Tsui Wang

The prevalence of chronic kidney disease (CKD) varies by race because of genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asian people, alters the enzyme's function in detoxifying alcohol-derived aldehydes, affecting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicate that diminished ALDH2 levels are linked to worse CKD outcomes, with correlations between ALDH2 expression, estimated glomerular filtration rate, urinary levels of acrolein - an aldehyde metabolized by ALDH2 - and fibrosis severity. In mouse models of unilateral ureteral obstruction and folic acid nephropathy, reduced ALDH2 levels and elevated acrolein were observed in kidneys, especially in ALDH2 Glu504Lys-knockin mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and coactivation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, and contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduced acrolein and mitigated fibrosis in both WT and Glu504Lys-knockin mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.

由于遗传和环境因素,慢性肾脏疾病(CKD)的发病率因种族而异。醛脱氢酶 2(ALDH2)中的 Glu504Lys 多态性在东亚人中很常见,它会改变该酶对酒精衍生的醛的解毒功能,从而影响肾功能。本研究调查了肾脏中 ALDH2 水平的变化与肾脏纤维化进展之间的关系。我们的临床数据表明,ALDH2 水平的降低与慢性肾脏病恶化的结果有关,ALDH2 表达、估计肾小球滤过率、尿液中的丙烯醛(一种由 ALDH2 代谢的醛)水平和纤维化严重程度之间存在相关性。在单侧输尿管梗阻和叶酸肾病小鼠模型中,观察到肾脏中 ALDH2 水平降低,丙烯醛升高,尤其是在 ALDH2 Glu504Lys 基因敲入小鼠中。从机理上讲,丙烯醛会改变丙酮酸激酶 M2,导致其核转位并共同激活 HIF-1α,使细胞代谢转向糖酵解,破坏线粒体功能,导致肾小管损伤和肾脏纤维化的进展。通过腺相关病毒载体增强 ALDH2 的表达,可减少丙烯醛并减轻野生型小鼠和 Glu504Lys 基因敲入小鼠的纤维化。这些发现强调了针对 CKD 中 ALDH2 和丙烯醛之间动态相互作用的潜在治疗意义。
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引用次数: 0
ATR inhibition radiosensitizes cells through augmented DNA damage and G2 cell cycle arrest abrogation. 抑制 ATR 可通过增强 DNA 损伤和抑制 G2 细胞周期停滞使细胞放射致敏。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-08 DOI: 10.1172/jci.insight.179599
Scott J Bright, Mandira Manandhar, David B Flint, Rishab Kolachina, Mariam Ben Kacem, David Kj Martinus, Broderick X Turner, Ilsa Qureshi, Conor H McFadden, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi

Ataxia telangiectasia and Rad3-related protein (ATR) is a key DNA damage response protein that facilitates DNA damage repair and regulates cell cycle progression. As such, ATR is an important component of the cellular response to radiation, particularly in cancer cells, which show altered DNA damage response and aberrant cell cycle checkpoints. Therefore, ATR's pharmacological inhibition could be an effective radiosensitization strategy to improve radiotherapy. We assessed the ability of an ATR inhibitor, AZD6738, to sensitize cancer cell lines of various histologic types to photon and proton radiotherapy. We found that radiosensitization took place through persistent DNA damage and abrogated G2 cell cycle arrest. We also found that AZD6738 increased the number of micronuclei after exposure to radiotherapy. We found that combining radiation with AZD6738 led to tumor growth delay and prolonged survival relative to radiation alone in a breast cancer model. Combining AZD6738 with photons or protons also led to increased macrophage infiltration at the tumor microenvironment. These results provide a rationale for further investigation of ATR inhibition in combination with radiotherapy and with other agents such as immune checkpoint blockade.

共济失调毛细血管扩张症和 Rad3 相关蛋白(ATR)是一种关键的 DNA 损伤反应蛋白,可促进 DNA 损伤修复并调节细胞周期的进展。因此,ATR 是细胞对辐射反应的重要组成部分,尤其是在 DNA 损伤反应发生改变和细胞周期检查点异常的癌细胞中。因此,ATR 的药理抑制可能是改善放疗的一种有效的放射增敏策略。我们评估了 ATR 抑制剂 AZD6738 使不同组织学类型的癌细胞系对光子和质子放疗敏感的能力。我们发现,放射增敏是通过持续的 DNA 损伤和 G2 细胞周期停滞来实现的。我们还发现,AZD6738 会增加接受放疗后的微核数量。我们发现,在乳腺癌模型中,放疗与 AZD6738 联合使用可延缓肿瘤生长,延长生存期,而单独使用则无法达到这一效果。将 AZD6738 与光子或质子结合使用还能增加巨噬细胞在肿瘤微环境中的浸润。这些结果为进一步研究 ATR 抑制与放疗和免疫检查点阻断等其他药物的联合应用提供了依据。
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引用次数: 0
Protein-truncating variant in APOL3 increases chronic kidney disease risk in epistasis with APOL1 risk alleles. APOL3 蛋白截短变体与 APOL1 风险等位基因的外显关系增加了慢性肾病的风险。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-08 DOI: 10.1172/jci.insight.181238
David Y Zhang, Michael G Levin, Jeffrey T Duda, Latrice G Landry, Walter R Witschey, Scott M Damrauer, Marylyn D Ritchie, Daniel J Rader

BACKGROUNDTwo coding alleles within the APOL1 gene, G1 and G2, found almost exclusively in individuals genetically similar to West African populations, contribute substantially to the pathogenesis of chronic kidney disease (CKD). The APOL gene cluster on chromosome 22 contains a total of 6 APOL genes that have arisen as a result of gene duplication.METHODSUsing a genome-first approach in the Penn Medicine BioBank, we identified 62 protein-altering variants in the 6 APOL genes with a minor allele frequency of >0.1% in a population of participants genetically similar to African reference populations and performed population-specific phenome-wide association studies.RESULTSWe identified rs1108978, a stop-gain variant in APOL3 (p.Q58*), to be significantly associated with increased CKD risk, even after conditioning on APOL1 G1/G2 carrier status. These findings were replicated in the Veterans Affairs Million Veteran Program and the All of Us Research Program. APOL3 p.Q58* was also significantly associated with a number of quantitative traits linked to CKD, including decreased kidney volume. This truncating variant contributed the most risk for CKD in patients monoallelic for APOL1 G1/G2, suggesting an epistatic interaction and a potential protective effect of wild-type APOL3 against APOL1-induced kidney disease.CONCLUSIONThis study demonstrates the utility of targeting population-specific variants in a genome-first approach, even in the context of well-studied gene-disease relationships.FUNDINGNational Heart, Lung, and Blood Institute (F30HL172382, R01HL169378, R01HL169458), Doris Duke Foundation (grant 2023-2024), National Institute of Biomedical Imaging and Bioengineering (P41EB029460), and National Center for Advancing Translational Sciences (UL1-TR-001878).

背景:APOL1基因中的两个编码等位基因G1和G2几乎只存在于与西非人群基因相似的个体中,它们对慢性肾脏病(CKD)的发病机制起着重要作用。22号染色体上的APOL基因簇共包含6个APOL基因,它们是基因复制的结果:方法:我们在宾夕法尼亚医学生物库中采用基因组优先方法,在与非洲参考人群基因相似的参与者人群中鉴定了六个 APOL 基因中 62 个小等位基因频率大于 0.1% 的改变蛋白质的变体,并进行了人群特异性全表型关联研究:结果:我们发现rs1108978是APOL3(p.Q58*)中的一个终止-增益变异,即使在APOL1 G1/G2携带者状态的条件下,它也与CKD风险的增加显著相关。这些发现在退伍军人事务百万退伍军人计划和我们所有人研究计划中得到了验证。APOL3 p.Q58*也与许多与慢性肾功能衰竭相关的定量特征有显著关联,包括肾脏体积的减少。这种截短变异在 APOL1 G1/G2 单拷贝患者中导致慢性肾脏病的风险最大,这表明野生型 APOL3 与 APOL1 诱导的肾脏病存在表观相互作用和潜在的保护作用:这项研究表明,即使在基因与疾病关系已得到充分研究的情况下,以基因组优先的方法针对人群特异性变异也是有用的:美国国家心肺血液研究所(F30HL172382、R01HL169378、R01HL169458)、多丽丝-杜克基金会(资助2023-0224)、美国国家生物医学成像和生物工程研究所(P41EB029460)、美国国家转化科学促进中心(UL1-TR-001878)。
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引用次数: 0
Neutrophils in nasal polyps exhibit transcriptional adaptation and proinflammatory role depend on local polyp milieu. 鼻息肉中的中性粒细胞表现出转录适应性,其促炎作用取决于当地息肉环境。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-03 DOI: 10.1172/jci.insight.184739
Chen Zhang, Qianqian Zhang, Jiani Chen, Han Li, Fuying Cheng, Yizhang Wang, Yingqi Gao, Yumin Zhou, Le Shi, Yufei Yang, Juan Liu, Kai Xue, Yaguang Zhang, Hongmeng Yu, Dehui Wang, Li Hu, Huan Wang, Xicai Sun

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory upper airway disease, divided into eosinophilic CRSwNP (eCRSwNP) and noneosinophilic CRSwNP (neCRSwNP) according to eosinophilic levels. Neutrophils are major effector cells in CRSwNP. but their role in different inflammatory environments remain largely unclear. We performed an integrated transcriptome analysis of polyp-infiltrating neutrophils from CRSwNP patients, using healthy donor blood as a control. Flow cytometry and in vitro studies showed that neutrophils are activated in both CRSwNP type. The scRNA-sequencing analysis demonstrated that neutrophils were classified into five functional subsets, with GBP5+ neutrophils occurring mainly in neCRSwNPs and a high proportion of CXCL8+ neutrophils in both subendotypes. GBP5+ neutrophils exhibited significant IFN-I pathway activity in neCRSwNPs. CXCL8+ neutrophils displayed increased neutrophil activation scores and mainly secrete Oncostatin M (OSM), which facilitates communication with other cells. In vitro experiments revealed that OSM could enhance IL-13- or IL-17-mediated immune responses in nasal epithelial cells and fibroblasts. Our findings revealed that neutrophils exhibited transcriptional plasticity and activation when exposed to polyp tissue and exert their proinflammatory role in the pathogenesis of CRSwNP by releasing OSM to interact with epithelial cells and fibroblasts in a manner dependent on the inflammatory milieu.

慢性鼻炎伴鼻息肉(CRSwNP)是一种上气道炎症性疾病,根据嗜酸性粒细胞水平分为嗜酸性鼻炎伴鼻息肉(eCRSwNP)和非嗜酸性鼻炎伴鼻息肉(neCRSwNP)。中性粒细胞是 CRSwNP 的主要效应细胞,但它们在不同炎症环境中的作用在很大程度上仍不清楚。我们以健康供血为对照,对 CRSwNP 患者息肉浸润中性粒细胞进行了综合转录组分析。流式细胞术和体外研究表明,CRSwNP 两种类型的中性粒细胞均被激活。scRNA 序列分析表明,中性粒细胞被分为五个功能亚群,其中 GBP5+ 中性粒细胞主要出现在 neCRSwNPs 中,两种亚型中都有很高比例的 CXCL8+ 中性粒细胞。GBP5+ 中性粒细胞在 neCRSwNPs 中表现出显著的 IFN-I 通路活性。CXCL8+嗜中性粒细胞的嗜中性粒细胞活化评分增加,并主要分泌Oncostatin M(OSM),OSM可促进与其他细胞的交流。体外实验显示,OSM 可增强鼻腔上皮细胞和成纤维细胞中 IL-13 或 IL-17 介导的免疫反应。我们的研究结果表明,中性粒细胞暴露于息肉组织时表现出转录可塑性和活化,并通过释放 OSM 与上皮细胞和成纤维细胞相互作用,以一种依赖于炎症环境的方式在 CRSwNP 的发病机制中发挥促炎作用。
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引用次数: 0
Effects of SIPA1L1 on trabecular meshwork extracellular matrix protein accumulation and cellular phagocytosis in POAG. SIPA1L1 对 POAG 小梁网细胞外基质蛋白积累和细胞吞噬功能的影响。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-03 DOI: 10.1172/jci.insight.174836
Chenyu Xu, Jiahong Wei, Dan Song, Siyu Zhao, Mingmin Hou, Yuchen Fan, Li Guo, Hao Sun, Tao Guo

Accumulation of extracellular matrix (ECM) proteins in trabecular meshwork (TM), which leads to increased outflow resistance of aqueous humor and consequently high intraocular pressure, is a major cause of primary open-angle glaucoma (POAG). According to our preliminary research, the RapGAP protein superfamily member, signal-induced proliferation-associated 1-like 1 protein (SIPA1L1), which is involved in tissue fibrosis, may have an impact on POAG by influencing ECM metabolism of TM. This study aims to confirm these findings and identify effects and cellular mechanisms of SIPA1L1 on ECM changes and phagocytosis in human TM (HTM) cells. Our results showed that the expression of SIPA1L1 in HTM cells was significantly increased by TGFβ2 treatment in Label-free quantitative proteomics. The aqueous humor and TM cells concentration of SIPA1L1 in POAG patients was higher than that of control. In HTM cells, TGFβ2 increased expression of SIPA1L1 along with accumulation of ECM, RhoA and p-Cofilin1. The effects of TGFβ2 were reduced by si-SIPA1L1. TGFβ2 decreased HTM cell phagocytosis by polymerizing cytoskeletal actin filaments, while si-SIPA1L1 increased phagocytosis by disassembling actin filaments. Simultaneously, overexpressing SIPA1L1 alone exhibited comparable effects to that of TGFβ2. Our studies demonstrate that SIPA1L1 not only promotes the production of ECM, but also inhibits its removal by reducing phagocytosis. Targeting SIPA1L1 degradation may become a significant therapy for POAG.

细胞外基质(ECM)蛋白在小梁网(TM)中积聚,导致房水外流阻力增加,从而导致高眼压,这是原发性开角型青光眼(POAG)的主要原因。根据我们的初步研究,参与组织纤维化的 RapGAP 蛋白超家族成员信号诱导增殖相关 1 样 1 蛋白(SIPA1L1)可能会通过影响 TM 的 ECM 代谢对 POAG 产生影响。本研究旨在证实这些发现,并确定 SIPA1L1 对人 TM(HTM)细胞中 ECM 变化和吞噬作用的影响及细胞机制。无标签定量蛋白质组学研究结果表明,TGFβ2处理可显著增加SIPA1L1在HTM细胞中的表达。POAG患者的房水和TM细胞中SIPA1L1的浓度高于对照组。在 HTM 细胞中,TGFβ2 增加了 SIPA1L1 的表达以及 ECM、RhoA 和 p-Cofilin1 的积累。si-SIPA1L1 可减少 TGFβ2 的影响。TGFβ2 通过聚合细胞骨架肌动蛋白丝来减少 HTM 细胞的吞噬作用,而 si-SIPA1L1 则通过分解肌动蛋白丝来增加吞噬作用。同时,单独过表达 SIPA1L1 与 TGFβ2 的效果相当。我们的研究表明,SIPA1L1 不仅能促进 ECM 的生成,还能通过减少吞噬作用抑制 ECM 的清除。以 SIPA1L1 降解为靶点可能成为治疗 POAG 的重要方法。
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引用次数: 0
Disruption of mitochondrial electron transport impairs urinary concentration via AMPK-dependent suppression of aquaporin-2. 线粒体电子传递的中断会通过 AMPK 依赖性抑制 aquaporin-2 来损害尿液浓度。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-03 DOI: 10.1172/jci.insight.182087
Joshua S Carty, Ryoichi Bessho, Yvonne Zuchowski, Jonathan B Trapani, Olena Davidoff, Hanako Kobayashi, Joseph T Roland, Jason A Watts, Andrew S Terker, Fabian Bock, Juan Pablo Arroyo, Volker H Haase

Urinary concentration is an energy-dependent process that minimizes body water loss by increasing aquaporin-2 (AQP2) expression in collecting duct (CD) principal cells. To investigate the role of mitochondrial (mt) ATP production in renal water clearance, we disrupted mt electron transport in CD cells by targeting ubiquinone (Q) binding protein QPC (UQCRQ), a subunit of mt complex III essential for oxidative phosphorylation. QPC-deficient mice produced less concentrated urine than controls, both at baseline and after type 2 vasopressin receptor stimulation with desmopressin. Impaired urinary concentration in QPC-deficient mice was associated with reduced total AQP2 protein levels in CD tubules, while AQP2 phosphorylation and membrane trafficking remained unaffected. In cultured inner medullary CD cells treated with mt complex III inhibitor antimycin A, the reduction in AQP2 abundance was associated with activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and was reversed by treatment with AMPK inhibitor SBI-0206965. In summary, our studies demonstrated that the physiological regulation of AQP2 abundance in principal CD cells was dependent on mt electron transport. Furthermore, our data suggested that oxidative phosphorylation in CD cells was dispensable for maintaining water homeostasis under baseline conditions, but necessary for maximal stimulation of AQP2 expression and urinary concentration.

尿液浓缩是一个依赖能量的过程,它通过增加集合管(CD)主细胞中的水蒸发素-2(AQP2)的表达来最大限度地减少体内水分的流失。为了研究线粒体(mt)产生 ATP 在肾脏水清除中的作用,我们通过靶向泛醌(Q)结合蛋白 QPC(UQCRQ)破坏了 CD 细胞中的线粒体电子传递,QPC 是线粒体复合体 III 的一个亚基,对氧化磷酸化至关重要。与对照组相比,QPC缺陷小鼠在基线和去氨加压素刺激2型血管加压素受体后产生的尿液浓度都较低。QPC 缺陷小鼠尿液浓缩功能受损与 CD 小管中 AQP2 蛋白总含量降低有关,而 AQP2 磷酸化和膜转运仍未受到影响。在用mt复合体III抑制剂抗霉素A处理的CD内髓细胞中,AQP2丰度的降低与5'单磷酸腺苷激活蛋白激酶(AMPK)的激活有关,AMPK抑制剂SBI-0206965可逆转AQP2丰度的降低。总之,我们的研究表明,CD主细胞中AQP2丰度的生理调节依赖于mt电子传递。此外,我们的数据还表明,在基线条件下,CD细胞中的氧化磷酸化对于维持水稳态是不可或缺的,但对于最大程度地刺激AQP2的表达和尿液浓度则是必要的。
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引用次数: 0
Dynamic Transition of Regulatory T Cells to Cytotoxic Phenotype Amid Systemic Inflammation in Graves' Ophthalmopathy. 巴塞杜氏眼病患者在全身炎症中调节性 T 细胞向细胞毒性表型的动态转变
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-03 DOI: 10.1172/jci.insight.181488
Zhong Liu, Shurui Ke, Zhuoxing Shi, Ming Zhou, Li Sun, Qihang Sun, Bing Xiao, Dongliang Wang, Yanjing Huang, Jinshan Lin, Huishi Wang, Qikai Zhang, Caineng Pan, Xuanwei Liang, Rongxin Chen, Zhen Mao, Xianchai Lin

Graves' disease (GD) is an autoimmune condition that can progress to Graves' Ophthalmopathy (GO), leading to irreversible damage to orbital tissues and potential blindness. The pathogenic mechanism is not fully understood. In this study, we conducted single-cell multi-omics analyses on healthy individuals, GD patients without GO, newly diagnosed GO patients, and treated GO patients. Our findings revealed gradual systemic inflammation during GO progression, marked by overactivation of cytotoxic effector T cell subsets, and expansion of specific T cell receptor clones. Importantly, we observed a decline in the immunosuppressive function of activated regulatory T cells (aTreg) accompanied by a cytotoxic phenotypic transition. In vitro experiments revealed that dysfunction and transition of GO-autoreactive Treg were regulated by the yinyang1 (YY1) upon secondary stimulation of thyroid stimulating hormone receptor (TSHR) under inflammatory conditions. Furthermore, adoptive transfer experiments of GO mouse model confirmed infiltration of these cytotoxic Treg into the orbital lesion tissues. Notably, these cells were found to upregulate inflammation and promote pathogenic fibrosis of orbital fibroblasts (OFs). Our results revealed the dynamic changes in immune landscape during GO progression and provided novel insights into the instability and phenotypic transition of Treg, offering potential targets for therapeutic intervention and prevention of autoimmune diseases.

巴塞杜氏病(GD)是一种自身免疫性疾病,可发展为巴塞杜氏眼病(GO),导致眼眶组织不可逆转的损伤和潜在的失明。其致病机制尚不完全清楚。在这项研究中,我们对健康人、未患巴塞杜氏眼病的广东患者、新诊断的巴塞杜氏眼病患者和接受治疗的巴塞杜氏眼病患者进行了单细胞多组学分析。我们的研究结果表明,在 GO 进展过程中,全身炎症逐渐加重,细胞毒性效应 T 细胞亚群过度活化,特异性 T 细胞受体克隆扩大。重要的是,我们观察到活化调节性T细胞(aTreg)的免疫抑制功能下降,并伴有细胞毒性表型转变。体外实验显示,在炎症条件下,当促甲状腺激素受体(TSHR)二次刺激时,GO-自反应Treg的功能障碍和转变受阴阳1(YY1)的调控。此外,GO小鼠模型的收养转移实验证实了这些细胞毒性Treg渗入眼眶病变组织。值得注意的是,这些细胞会上调炎症反应,并促进眼眶成纤维细胞(OFs)的致病性纤维化。我们的研究结果揭示了GO进展过程中免疫格局的动态变化,并对Treg的不稳定性和表型转变提供了新的见解,为治疗干预和预防自身免疫性疾病提供了潜在靶点。
{"title":"Dynamic Transition of Regulatory T Cells to Cytotoxic Phenotype Amid Systemic Inflammation in Graves' Ophthalmopathy.","authors":"Zhong Liu, Shurui Ke, Zhuoxing Shi, Ming Zhou, Li Sun, Qihang Sun, Bing Xiao, Dongliang Wang, Yanjing Huang, Jinshan Lin, Huishi Wang, Qikai Zhang, Caineng Pan, Xuanwei Liang, Rongxin Chen, Zhen Mao, Xianchai Lin","doi":"10.1172/jci.insight.181488","DOIUrl":"https://doi.org/10.1172/jci.insight.181488","url":null,"abstract":"<p><p>Graves' disease (GD) is an autoimmune condition that can progress to Graves' Ophthalmopathy (GO), leading to irreversible damage to orbital tissues and potential blindness. The pathogenic mechanism is not fully understood. In this study, we conducted single-cell multi-omics analyses on healthy individuals, GD patients without GO, newly diagnosed GO patients, and treated GO patients. Our findings revealed gradual systemic inflammation during GO progression, marked by overactivation of cytotoxic effector T cell subsets, and expansion of specific T cell receptor clones. Importantly, we observed a decline in the immunosuppressive function of activated regulatory T cells (aTreg) accompanied by a cytotoxic phenotypic transition. In vitro experiments revealed that dysfunction and transition of GO-autoreactive Treg were regulated by the yinyang1 (YY1) upon secondary stimulation of thyroid stimulating hormone receptor (TSHR) under inflammatory conditions. Furthermore, adoptive transfer experiments of GO mouse model confirmed infiltration of these cytotoxic Treg into the orbital lesion tissues. Notably, these cells were found to upregulate inflammation and promote pathogenic fibrosis of orbital fibroblasts (OFs). Our results revealed the dynamic changes in immune landscape during GO progression and provided novel insights into the instability and phenotypic transition of Treg, offering potential targets for therapeutic intervention and prevention of autoimmune diseases.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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