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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。
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引用次数: 0
Targeted Bmal1 restoration in muscle prolongs lifespan with systemic health effects in aging model. 在衰老模型中,肌肉中 Bmal1 的靶向修复可延长寿命,并对全身健康产生影响。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/jci.insight.174007
Miguel A Gutierrez-Monreal, Christopher A Wolff, Eduardo E Rijos, Mark R Viggars, Collin M Douglas, Vishwajeeth Pagala, Junmin Peng, Liam C Hunt, Haocheng Ding, Fabio Demontis, Zhiguang Huo, Karyn A Esser

Disruption of the circadian clock in skeletal muscle worsens local and systemic health, leading to decreased muscle strength, metabolic dysfunction, and aging-like phenotypes. Whole-body knockout mice that lack Bmal1, a key component of the molecular clock, display premature aging. Here, by using adeno-associated viruses, we rescued Bmal1 expression specifically in the skeletal muscle fibers of Bmal1-KO mice and found that this engaged the circadian clock and clock output gene expression contributing to extended lifespan. Time course phenotypic analyses found that muscle strength, mobility, and glucose tolerance were improved with no effects on muscle mass, fiber size or type. A multi-omics approach at two ages further determined that restored muscle Bmal1 improved glucose handling pathways while concomitantly reducing lipid and protein metabolic pathways. The improved glucose tolerance and metabolic flexibility resulted in the systemic reduction of inflammatory signatures across peripheral tissues including liver, lung, and white adipose fat. Together, these findings highlight the critical role of muscle Bmal1 and downstream target genes for skeletal muscle homeostasis with considerable implications for systemic health.

骨骼肌中昼夜节律时钟的破坏会恶化局部和全身健康,导致肌肉力量下降、代谢功能障碍和类似衰老的表型。全身基因敲除小鼠缺乏分子时钟的关键成分Bmal1,会出现早衰。在这里,我们通过使用腺相关病毒,特异性地挽救了 Bmal1-KO 小鼠骨骼肌纤维中 Bmal1 的表达,并发现这参与了昼夜节律时钟和时钟输出基因的表达,有助于延长寿命。时程表型分析发现,小鼠的肌肉力量、活动能力和葡萄糖耐量得到了改善,但肌肉质量、纤维大小或类型没有受到影响。两个年龄段的多组学方法进一步确定,恢复肌肉 Bmal1 改善了葡萄糖处理途径,同时减少了脂质和蛋白质代谢途径。葡萄糖耐量和代谢灵活性的改善导致肝脏、肺部和白色脂肪等外周组织炎症特征的系统性减少。总之,这些发现凸显了肌肉 Bmal1 和下游靶基因对骨骼肌平衡的关键作用,对全身健康具有重大意义。
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引用次数: 0
The DNA sensor AIM2 mediates psoriasiform inflammation by inducing type 3 immunity. DNA 传感器 AIM2 通过诱导 3 型免疫介导牛皮癣炎症。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/jci.insight.171894
Timna Varela Martins, Bruno Marcel Silva de Melo, Juliana Escher Toller-Kawahisa, Gabriel Victor Lucena da Silva, Conceição Elidianne Aníbal Silva, Isadora Marques Paiva, Gabriel Azevedo Públio, Marcos Henrique Rosa, Cacilda da Silva Souza, Dario Simões Zamboni, Fernando Q Cunha, Thiago Mattar Cunha, Bernhard Ryffel, Nicolas Riteau, José C Alves-Filho

Psoriasis is a chronic and recurrent inflammatory skin disease characterized by abnormal proliferation and differentiation of keratinocytes and activation of immune cells. However, the molecular driver that triggers this immune response in psoriatic skin remains unclear. The inflammation-related gene absent in melanoma 2 (AIM2) was identified as a susceptibility gene/locus associated with psoriasis. In this study, we investigated the role of AIM2 in the pathophysiology of psoriasis. We found elevated levels of mitochondrial DNA in patients with psoriasis, along with high expression of AIM2 in both the human psoriatic epidermis and a mouse model of psoriasis induced by topical imiquimod (IMQ) application. Genetic ablation of AIM2 reduced the development of IMQ-induced psoriasis by decreasing the production of type 3 cytokines (such as IL-17A and IL-23) and infiltration of immune cells into the inflammatory site. Furthermore, we demonstrate that IL-17A induced AIM2 expression in keratinocytes. Finally, the genetic absence of inflammasome components downstream AIM2, ASC, and caspase-1 alleviated IMQ-induced skin inflammation. Collectively, our data show that AIM2 is involved in developing psoriasis through its canonical activation.

银屑病是一种慢性和复发性炎症性皮肤病,其特征是角质形成细胞异常增殖和分化以及免疫细胞被激活。然而,引发银屑病皮肤这种免疫反应的分子驱动因素仍不清楚。黑色素瘤中缺失的炎症相关基因 2(AIM2)被确定为与银屑病相关的易感基因/病灶。本研究调查了 AIM2 在银屑病病理生理学中的作用。我们发现银屑病患者的线粒体 DNA 水平升高,同时 AIM2 在人类银屑病表皮和外用咪喹莫特(IMQ)诱导的银屑病小鼠模型中均有高表达。通过减少 3 型细胞因子(如 IL-17A 和 IL-23)的产生和免疫细胞对炎症部位的浸润,基因消减 AIM2 减少了 IMQ 诱导的银屑病的发展。此外,我们还证明了 IL-17A 能诱导角质形成细胞中 AIM2 的表达。最后,遗传性缺失炎性体下游成分 AIM2、ASC 和 caspase-1 可减轻 IMQ 诱导的皮肤炎症。总之,我们的数据表明,AIM2 通过其典型激活参与了银屑病的发病。
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引用次数: 0
Sublingual immune cell clusters and dendritic cell distribution in the oral cavity. 口腔中的舌下免疫细胞群和树突状细胞分布。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/jci.insight.167373
Yutaka Kusumoto, Mizuki Ueda, Mayuko Hashimoto, Haruka Takeuchi, Naoko Okada, Junya Yamamoto, Akiko Nishii, Atsuki Fujino, Akiho Kurahashi, Momoka Satoh, Yuki Iwasa, Koki Okamura, Karin Obazaki, Ryoto Kumagai, Naruya Sakamoto, Yuto Tanaka, Yukika Kamiya, Tetsushi Hoshida, Tsuneyasu Kaisho, Hiroaki Hemmi, Tomoya Katakai, Tetsuya Honda, Junichi Kikuta, Kosuke Kataoka, Ryoyo Ikebuchi, Taiki Moriya, Takahiro Adachi, Takeshi Watanabe, Masaru Ishii, Atsushi Miyawaki, Kenji Kabashima, Tatyana Chtanova, Michio Tomura

The oral mucosa is the first line of defense against pathogenic bacteria and plays a vital role in maintaining tolerance to food antigens and commensal bacteria. We used CD11c reporter mice to visualize dendritic cells (DCs), a key immune cell population, in the oral cavity. We identified differences in DC density in each oral tissue region. Sublingual immune cell clusters (SLICs) extended from the lamina propria to the epithelium, where DCs and T cells resided in close contact with each other and innate lymphoid cells. Targeted in situ photolabeling revealed that the SLICs comprised mostly CD11c+CD11b+ DCs and were enriched for cDC1s and Langerhans cells. Although the frequency of T cell subsets was similar within and outside the SLICs, tissue-resident memory T cells were significantly enriched within the clusters and cluster size increased in response to inflammation. Collectively, we found that SLICs form a unique microenvironment that facilitates T cell-DC interactions in the steady state and during inflammation. Since the oral mucosa is an important target for needle-free vaccination and sublingual immunotherapy to induce tolerogenic responses, the insight into the localized immunoregulation provided in this study may accelerate the development of these approaches.

口腔黏膜是抵御病原菌的第一道防线,在维持对食物抗原和共生细菌的耐受性方面起着至关重要的作用。我们使用 CD11c 报告小鼠来观察口腔中的树突状细胞(DC),这是一种关键的免疫细胞群。我们发现每个口腔组织区域的树突状细胞密度存在差异。舌下免疫细胞簇(SLICs)从固有层延伸到上皮细胞,在这些细胞簇中,DC 和 T 细胞彼此密切接触,并与先天性淋巴细胞(ILCs)共存。靶向原位光标记显示,SLICs 主要由 CD11c+CD11b+ DCs 组成,并富含 cDC1s 和朗格汉斯细胞。虽然 SLIC 内外的 T 细胞亚群频率相似,但组织常驻记忆 T 细胞明显富集在细胞簇内,而且细胞簇的大小随炎症反应而增大。总之,我们发现 SLICs 形成了一种独特的微环境,有利于 T 细胞-DC 在稳态和炎症期间的相互作用。由于口腔粘膜是无针疫苗接种和舌下免疫疗法诱导耐受性反应的重要目标,本研究提供的对局部免疫调节的新见解可能会加速这些方法的开发。
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