American Journal of Pathology最新文献_第6页

Loss of Aquaporin-1 in Tumor Cells Fosters Intrahepatic Cholangiocarcinoma Progression 肿瘤细胞中水通道蛋白-1的缺失促进肝内胆管癌的进展。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2026-02-01 Epub Date: 2025-11-07 DOI: 10.1016/j.ajpath.2025.10.007

César I. Gaspari , Carine Beaupere , Seth Richard , Estanislao Peixoto , Bouchra Lekbaby , Mirko Minini , Branko Dubravcic , Javier Vaquero , Marie Vallette , Ander Arbelaiz , Marion Janona , Corentin Louis , Pauline Le Gall , Cédric Coulouarn , Julieta Marrone , Juan E. Abrahante , Raúl A. Marinelli , Sergio A. Gradilone , Laura Fouassier

Aquaporin-1 (AQP1) is a water channel expressed by cholangiocytes described to modulate cell proliferation and invasion in several cancers. But the role of AQP1 in cholangiocarcinoma (CCA) remains unknown. The aim was to study the function of AQP1 in CCA. AQP1 expression was evaluated in 39 intrahepatic CCA (iCCA) specimens from transcriptomic data. AQP1-knockout in HuCCT1 iCCA cells was achieved by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9). Next-generation sequencing (RNA sequencing) was performed to study the consequences of AQP1 inhibition on cell phenotype. Epithelial-mesenchymal transition (EMT), cell migration and proliferation, and signaling pathways were evaluated by live-cell imaging system, quantitative RT-PCR, Western blot, and immunostaining. In vivo experiments were performed using a xenograft CCA model. In human iCCA, low AQP1 expression correlated with reduced overall survival. In vivo, CCA cells depleted for AQP1 displayed a higher tumorigenic potential than control cells. In vitro, RNA-sequencing analysis of AQP1-depleted CCA cells showed signatures of tumor progression, including EMT. Indeed, AQP1-depleted cells showed a cell dispersion phenotype, loss of the junction protein E-cadherin, and higher expression of vimentin and zinc finger E-box binding homeobox 1 (ZEB1), along with stemness traits. Functionally, loss of AQP1 is associated with increased cell migration and proliferation. Moreover, an activation of the insulin-like growth factor 2/insulin-like growth factor 1 receptor/insulin receptor pathway was found in AQP1-depleted CCA cells. The data suggest that AQP1 acts as a tumor suppressor in iCCA.

水通道蛋白-1 （AQP1）是一种由胆管细胞表达的水通道，在多种癌症中被描述为调节细胞增殖和侵袭。但AQP1在胆管癌（CCA）中的作用尚不清楚。我们的目的是研究AQP1在CCA中的功能。通过转录组学数据评估39例肝内CCA （iCCA）标本中AQP1的表达。通过CRISPR-Cas9在HuCCT1 iCCA细胞中实现AQP1-KO。下一代测序（RNAseq）研究AQP1抑制对细胞表型的影响。采用诱导细胞活细胞成像系统、RT-qPCR、western-blot和免疫染色评价上皮-间质转化（Epithelial-mesenchymal transition， EMT）、细胞迁移增殖和信号通路。体内实验采用异种移植CCA模型。在人类iCCA中，AQP1的低表达与总生存率降低相关。在体内，AQP1缺失的CCA细胞比对照细胞表现出更高的致瘤潜能和肿瘤负荷。体外，aqp1缺失的CCA细胞的RNA-seq分析显示肿瘤进展的特征，包括EMT。事实上，aqp1缺失的细胞表现出表型变化，诱导细胞分散，细胞-细胞连接蛋白E-cadherin的缺失，vimentin和ZEB1的高表达，以及干性性状。功能上，AQP1的缺失与细胞迁移和增殖增加有关。此外，我们发现在aqp1缺失的CCA细胞中IGF2/IGF1R/IR通路被激活。我们的数据表明AQP1在iCCA中起肿瘤抑制作用。

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引用次数: 0

PathViT Model for Automated Disease Classification from Skeletal Muscle Histopathology PathViT：骨骼肌组织病理学自动疾病分类。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2026-02-01 Epub Date: 2025-11-06 DOI: 10.1016/j.ajpath.2025.10.009

Taymaz Akan , Sait Alp , Richa Aishwarya , Diensn G. Xing , Destyn Dicharry , Md. Shenuarin Bhuiyan , Mohammad Alfrad Nobel Bhuiyan

Analyzing skeletal muscle pathology from histological images is labor intensive (requiring manual cell counting, segmentation, and thresholding), time consuming, and prone to inter- and intrauser variability, influencing the accuracy and consistency of diagnoses. To address these difficulties, PathViT, a transformer-based deep-learning model, was designed to automatically distinguish between healthy and diseased muscle fibers, with the aims of reducing human intervention, minimizing subjectivity and variability, and significantly decreasing analysis time compared to conventional manual methods. Skeletal muscle pathology is characterized by changes in myofiber cross-sectional area, increased central nuclei, and structural disruptions in sarcomeres. To investigate these changes in myofiber size, wheat germ agglutinin staining and digital histopathology of skeletal muscle (quadriceps, gastrocnemius, tibialis anterior, extensor digitorum longus, and soleus) was utilized to classify diseased tissue [amyotrophic lateral sclerosis (SOD1∗G93A) and type 1 diabetes (Akita)] versus nondiseased controls. The performance of PathViT in distinguishing diseased versus nondiseased muscle fibers was compared with that of state-of-the-art deep-learning models. PathViT classified healthy and diseased muscle fibers with 96% accuracy, outperforming the other models. This approach enhanced scalability and diagnostic accuracy and decreased variability, making PathViT a potentially powerful biomedical research and clinical tool.

从组织学图像中分析骨骼肌病理是一个劳动密集型的过程，容易受到用户之间和用户内部差异的影响，从而影响诊断的准确性和一致性——传统的技术，如基于imagej的工具，需要手动进行细胞计数、分割和阈值设置。因此，它们既耗时又会产生不同的结果。为了解决这些困难，我们开发了PathViT，这是一种基于转换器的深度学习模型，用于病理图像的自动分类。骨骼肌病理的特点是肌纤维横截面积改变，中央核增加，肌节结构破坏。为了研究这些肌纤维大小的变化，我们使用小麦胚芽凝集素（WGA）染色的不同骨骼肌（股四头肌、腓肠肌、胫骨前肌、指长伸肌和比目鱼肌）的组织病理学图像来对肌萎缩性侧索硬化症（ALS）、糖尿病和健康对照进行分类。PathVit可以自动区分健康和病变肌纤维，减少人为干预，最大限度地减少主观性和可变性，与传统的人工方法相比，显著减少分析时间。我们使用野生型和疾病模型（ALS为G93A*SOD1, 1型糖尿病为Akita）的wga染色骨骼肌图像，对PathViT与最先进的深度学习模型进行了评估。PathViT对健康和病变肌纤维的分类准确率为96%，优于所有其他模型。与人工方法相比，PathVit减少了人为干预、主观性、可变性和分析时间。这种方法提高了可扩展性、诊断准确性和可变性，使PathViT成为强大的生物医学研究和临床工具。

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引用次数: 0

Quantitative 3D Imaging of Mouse and Human Intrahepatic Bile Ducts in Homeostasis and Liver Injury 小鼠和人肝内胆管稳态和肝损伤的定量三维成像

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2026-02-01 Epub Date: 2026-01-20 DOI: 10.1016/j.ajpath.2025.10.008

Hannah R. Hrncir , Brianna Goodloe , Sergei Bombin , Siyang J. Sun , Zelin Zhang , Anant Madabhushi , Adam D. Gracz

Intrahepatic bile ducts (IHBDs) form a complex hierarchical network essential for liver function. The remodeling and expansion of this network during ductular reaction (DR) are hallmarks of liver disease that can be key indicators of disease severity. Conventional histology fails to capture the full extent of IHBD structural changes after injury due to the complex three-dimensional (3D) organization of the IHBD network that limits understanding of DR, especially in human tissue. A major barrier to leveraging 3D imaging as a diagnostic tool is the absence of standardized pipelines for IHBD imaging and analysis. This work establishes a robust 3D IHBD imaging and analysis workflow, applying it to both mouse and human liver tissues. This pipeline enables quantification of tissue and individual duct (“segment”) level features and identifies features of invasive and noninvasive DR. In mouse models, we uncover regional phenotypes, including IHBD diverticula-like structures after duct blockage and the formation of anastomosed clusters after hepatocellular injury. Finally, this 3D imaging and analysis workflow is applied to quantify IHBD networks in human liver tissue. This work deepens our understanding of IHBD architecture in homeostasis and injury, laying the groundwork for advanced phenotyping of IHBD morphologies in mice and humans with relevance to next-generation experimental and diagnostic approaches to liver disease.

肝内胆管（IHBDs）形成了一个复杂的分层网络，对肝功能至关重要。导管反应（DR）期间该网络的重塑和扩张是肝脏疾病的标志，也是疾病严重程度的关键指标。由于IHBD网络的复杂三维（3D）组织限制了对DR的理解，特别是在人体组织中，传统组织学无法捕捉损伤后IHBD结构变化的全部程度。利用3D成像作为诊断工具的一个主要障碍是缺乏标准化的IHBD成像和分析管道。这项工作建立了一个强大的3D IHBD成像和分析工作流程，将其应用于小鼠和人类肝脏组织。该管道能够量化组织和单个管道（“段”）水平的特征，并识别侵入性和非侵入性dr的特征。在小鼠模型中，我们揭示了区域表型，包括管道阻塞后的IHBD憩室样结构和肝细胞损伤后吻合簇的形成。最后，该3D成像和分析工作流程被用于量化人肝组织中的IHBD网络。这项工作加深了我们对体内平衡和损伤中IHBD结构的理解，为小鼠和人类中IHBD形态学的高级表型研究奠定了基础，并与下一代肝脏疾病的实验和诊断方法相关。

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引用次数: 0

Targeting RORγ to Boost Regulatory T cells and Ameliorate Diabetic Retinopathy in Mice 靶向RORγ促进调节性T细胞和改善小鼠糖尿病视网膜病变。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2026-02-01 Epub Date: 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.006

Devy Deliyanti, Varaporn Suphapimol, Phoebe Ang, Abhirup Jayasimhan, Jennifer L. Wilkinson-Berka

Diabetic retinopathy, a leading cause of blindness, features damage to the retinal vasculature, where T-cell–mediated inflammation is increasingly recognized as an important contributor. Retinoic acid receptor-related orphan receptor gamma (RORγ) plays a key role in regulating the balance between anti-inflammatory regulatory T cells (Tregs) expressing the transcription factor Foxp3 and proinflammatory Th17 cells. It was hypothesized that inhibiting RORγ with SR2211, targeting both RORγ and its isoform RORγt, increases Tregs and reduces Th17 cells, resulting in reduced inflammation and vasculopathy in a streptozotocin-induced model of diabetic retinopathy. Mice expressing Foxp3 as a red fluorescent protein were treated with SR2211 for 26 weeks of diabetes, and comparisons made to diabetic mice administered vehicle and non-diabetic control mice. In blood and lymphoid tissues of diabetic mice, treatment with SR2211 restored the number of Tregs and reduced Th17 cells to the levels of diabetic mice + vehicle. In the retina of diabetic mice, treatment with SR2211 increased Tregs and reduced the activation of microglia cells, the expression of proinflammatory factors including IL-17A, IL-6 and tumor necrosis factor, vascular leakage, vascular endothelial growth factor, and acellular capillaries, compared with diabetic mice + vehicle. These findings indicate the ability of RORγ/RORγt inhibition to modulate specific T-cell responses and suppress microglia activation to reduce inflammation and vascular damage in diabetic retinopathy.

糖尿病视网膜病变是导致失明的主要原因之一，其特征是视网膜脉管系统受损，其中T细胞介导的炎症越来越被认为是一个重要的因素。视黄酸受体相关孤儿受体γ (RORγ)在调节表达转录因子Foxp3的抗炎调节性T细胞（Tregs）和促炎Th17细胞之间的平衡中起关键作用。我们假设SR2211抑制RORγ，同时靶向RORγ及其亚型RORγ γt，可以增加Tregs并减少Th17细胞，从而减少链佐菌素诱导的糖尿病视网膜病变模型中的炎症和血管病变。将表达Foxp3为红色荧光蛋白的小鼠用SR2211治疗糖尿病26周，并与糖尿病小鼠和非糖尿病对照组小鼠进行比较。在糖尿病小鼠的血液和淋巴组织中，用SR2211治疗可以恢复treg的数量，并将Th17细胞降低到糖尿病小鼠+对照体的水平。在糖尿病小鼠的视网膜中，与糖尿病小鼠+对照体相比，SR2211处理增加了Tregs，降低了小胶质细胞的活化，降低了促炎因子（包括白细胞介素- 17a、白细胞介素-6和肿瘤坏死因子）的表达，降低了血管渗漏、血管内皮生长因子和脱细胞毛细血管的表达。这些发现表明，RORγ/RORγ γt抑制能够调节特异性t细胞反应，抑制小胶质细胞激活，从而减少糖尿病视网膜病变的炎症和血管损伤。

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引用次数: 0

Leukocytic Dopamine D2 Receptors as Biomarkers for Brain Dopamine Levels in Parkinson Disease. 白细胞多巴胺D2受体作为帕金森病脑多巴胺水平的生物标志物。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2026-02-01 DOI: 10.1016/j.ajpath.2026.01.003

Christina A Nelson, J Daniel Obray, Charles R Roll, Pacen E Williams, Kathryn J Smith, William T Harris, Caylor W Hafen, Matthew D Burris, Kim H Manwaring, Daniel N Adams, K Scott Weber, Sandra Hope, Ulrike H Mitchell, Jordan T Yorgason, Scott C Steffensen

Having the ability to objectively index dopamine (DA) levels in the brain with a peripheral biomarker of brain DA would enable the objective monitoring of the progression of Parkinson disease (PD) and other DA-dependent disorders. This study investigates this potential biomarker using a DA-depletion approach, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model and subjects with PD, which are well-known models of DA depletion in the midbrain of rodents and humans, respectively. MPTP-induced DA depletion in the substantia nigra compacta resulted in a significant decrease in DA and norepinephrine levels in the blood. The proportion of dopamine D2 receptor (D2R)-expressing leukocytes progressively decreased (specifically B and T cells) during the DA depletion. Subjects with PD displayed significantly decreased D2R expression in B and T cells, and increased levels in epinephrine, DA, norepinephrine, and levodopa, compared with control subjects. A significant negative correlation was found between blood levodopa and D2R expression in classical monocytes, which correlated mildly with blood DA levels. The modulation of peripheral D2Rs in PD and MPTP seen in this study demonstrates that substantia nigra compacta dopamine depletion in humans and rodents does manifest in the periphery. Although this study did not provide a clear narrative of how nigral and peripheral dopamine systems mirror each other, the results give evidence that peripheral D2Rs may be both biomarkers and important substrates for treatment of dopamine-dependent disorders.

利用脑多巴胺的外周生物标志物客观地索引大脑中的多巴胺水平，将使客观监测帕金森病（PD）和其他多巴胺依赖性疾病的进展成为可能。本研究利用多巴胺耗竭方法，1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）神经毒素模型和PD受试者，分别研究了啮齿动物和人类中脑多巴胺耗竭模型，研究了这一潜在的生物标志物。mptp诱导的黑质致密（SNc）多巴胺耗竭导致血液中多巴胺和去甲肾上腺素水平显著降低。多巴胺d2亚型受体（D2R）表达的白细胞比例（特别是B细胞和T细胞）在DA耗竭过程中逐渐减少。与对照组相比，帕金森患者的B细胞和T细胞中D2R表达明显降低，肾上腺素、多巴胺、去甲肾上腺素和左旋多巴水平升高。我们发现血左旋多巴与经典单核细胞D2R表达呈显著负相关，与血多巴胺水平轻度相关。本研究发现PD和MPTP中外周D2Rs的调节表明，人类和啮齿动物的SNc多巴胺耗竭确实表现在外周。虽然这项研究并没有提供关于黑质和外周多巴胺系统如何相互镜像的清晰叙述，但结果表明外周D2Rs可能既是生物标志物，也是治疗多巴胺依赖性疾病的重要底物。

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引用次数: 0

Hepatocyte-Specific MET Deletion Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice 肝细胞特异性MET缺失加剧对乙酰氨基酚诱导的小鼠肝毒性。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2026-02-01 Epub Date: 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.010

Siddhi Jain , Ranjan Mukherjee , Gillian Williams , Jia-Jun Liu , Lanuza A.P. Faccioli , Zhiping Hu , Rodrigo M. Florentino , George K. Michalopoulos , Alejandro Soto-Gutierrez , Silvia Liu , Joseph Locker , Bharat Bhushan

Despite the well-known role of MET in liver regeneration after partial hepatectomy, its role in the clinically relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from partial hepatectomy because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET knockout (MET KO) mice were administered a toxic dose of APAP and assessed for liver injury/regeneration parameters. MET deletion strikingly exacerbated the initial hepatotoxicity and consequentially impaired the compensatory proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced c-Jun N-terminal kinase (JNK) activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative damage, releasing apoptosis-inducing factor into cytosol. Excess JNK activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET signaling. Pharmacologic activation of AKT reduced JNK activation and hepatotoxicity in MET KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling but also activation of cell death/senescence pathways along with an impaired unfolded protein response in MET KO mice. Analysis of published single-nucleus RNA-sequencing data showed that proliferation in livers from patients with APAP-induced acute liver failure was associated with strong activation of hepatocyte growth factor/MET signaling in hepatocytes, with spatial transcriptomics showing striking induction of hepatocyte growth factor surrounding the necrotic zones. Interestingly, 35% of the genes altered in human acute liver failure were regulated by MET in the mouse AILI model. The current study shows that MET is crucial for restraining hepatotoxicity after APAP overdose via inhibition of the mitochondrial cell death signaling pathway.

尽管MET在部分肝切除术（PHx）后肝脏再生中的作用众所周知，但其在临床相关的对乙酰氨基酚（APAP）诱导的肝损伤（AILI）模型中的作用仍未被探索。aii明显不同于PHx，因为它与大量肝坏死有关。本研究旨在明确MET在AILI中的作用。给肝细胞特异性MET-KO小鼠注射毒性剂量的APAP，并评估肝损伤/再生参数。MET缺失显著加剧了最初的肝毒性，并因此损害了代偿性增殖反应，最终导致显著的死亡率。在机制上，MET缺失增强了jnk活化及其线粒体易位，导致线粒体过度氧化损伤，将细胞死亡诱导剂AIF释放到细胞质中。过量的JNK激活归因于AKT在缺乏met信号的情况下对JNK的抑制活性降低。AKT的药理激活降低了MET-KO小鼠的jnk激活和肝毒性。rna测序/免疫印迹不仅显示MET-KO小鼠的增殖/生存信号被抑制，而且细胞死亡/衰老途径被激活，同时未折叠蛋白反应受损。对已发表的单核rna测序数据的分析显示，apap诱导的ALF患者肝脏中的增殖与肝细胞中HGF/MET信号的强烈激活有关，空间转录组学显示坏死区周围HGF的显著诱导。有趣的是，在小鼠aili模型中，人类alf中35%的基因改变受到MET的调节。总之，本研究表明MET通过抑制线粒体细胞死亡信号通路，对抑制APAP过量后的肝毒性至关重要。

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引用次数: 0

Macrophages Are Critical Inducers of Bleomycin-Induced Fibrosis in a Systemic Scleroderma Model 巨噬细胞是博莱霉素诱导的系统性硬皮病模型纤维化的关键诱导因子

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2026-02-01 Epub Date: 2026-01-20 DOI: 10.1016/j.ajpath.2025.09.009

Blandine Baffert , Kevin Schneider , Audrey Wetzel , Ludivine Dal Zuffo , Cécile Chagué , Eléa Mitifiot , Francis Bonnefoy , Alicja Kuzniewska , Philippe Saas , Jamal Bamoulid , Gwenael Rolin , Sylvain Perruche , Sanja Arandjelovic

Macrophages are critical regulators of inflammation with an essential role in maintaining and re-establishing homeostasis after inflammatory insults. However, excessive macrophage activation could promote fibrosis, highlighting their potential as a therapeutic target in chronic inflammatory diseases. Two preclinical models of systemic sclerosis, bleomycin-induced systemic scleroderma and sclerodermatous graft-versus-host disease, were used to analyze the role of macrophages in the establishment of fibrosis. In both models, macrophage numbers increase in the skin and lungs, in association with elevated collagen content and correlating with fibrosis development. These macrophages had a Ly6c^lowCD206⁺MerTk⁺ phenotype, suggesting a profibrotic role during disease progression. Using macrophage depletion and differentiation blocking approaches, this work shows that reduced macrophage accumulation effectively prevented bleomycin-induced fibrosis development. Direct profibrotic activity of bleomycin-exposed macrophages was revealed by s.c. macrophage injections in naïve mice, which was sufficient to induce systemic fibrosis. Finally, bleomycin-treated primary mouse and human macrophages display reduced clearance of apoptotic cells and secrete factors that promote fibroblast activation and collagen production. Metabolic and mitochondrial dysfunction, changes in receptor shedding, and cytoskeletal reorganization in bleomycin-treated macrophages further contribute to their impaired efferocytosis and enhanced profibrotic activity. Collectively, this work identifies macrophages as critical promoters of tissue fibrosis and suggests that inhibition of macrophage activation represents a new potent therapeutic avenue in efforts to reverse fibrosis associated with chronic inflammation.

巨噬细胞是炎症的关键调节因子，在炎症损伤后维持和重建体内平衡中发挥重要作用。然而，过度的巨噬细胞激活可促进纤维化，突出了它们作为慢性炎症性疾病治疗靶点的潜力。采用博莱霉素诱导的系统性硬皮病和硬皮病移植物抗宿主病两种系统性硬化症临床前模型，分析巨噬细胞在纤维化建立中的作用。在两种模型中，皮肤和肺部的巨噬细胞数量增加，与胶原含量升高有关，并与纤维化发展相关。这些巨噬细胞具有Ly6clowCD206+MerTk+表型，表明在疾病进展过程中具有促纤维化作用。通过巨噬细胞消耗和分化阻断方法，这项工作表明减少巨噬细胞积累有效地阻止了博莱霉素诱导的纤维化发展。在naïve小鼠体内注射s.c.巨噬细胞，发现博莱霉素暴露的巨噬细胞具有直接促纤维化活性，足以诱导全身纤维化。最后，博莱霉素处理的原代小鼠和人巨噬细胞对凋亡细胞和促进成纤维细胞活化和胶原生成的分泌因子的清除减少。博莱霉素处理巨噬细胞的代谢和线粒体功能障碍、受体脱落的变化和细胞骨架重组进一步导致其efferocytosis受损和纤维化活性增强。总的来说，这项工作确定了巨噬细胞是组织纤维化的关键促进因子，并表明抑制巨噬细胞激活代表了一种新的有效治疗途径，可以逆转与慢性炎症相关的纤维化。

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引用次数: 0

Stimulator of Interferon Genes Is a Fine-Tuner, but Not a Prime Mover, of Kidney Inflammation 干扰素基因的刺激因子是肾脏炎症的微调者，但不是原动力

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2026-02-01 Epub Date: 2026-01-20 DOI: 10.1016/j.ajpath.2025.10.013

Madiha Zahra Syeda , Emily S.H. Yeung , Lisa Y.Q. Hong , Suzanne L. Advani , Youan Liu , Laurette Geldenhuys , Ferhan S. Siddiqi , Veera Ganesh Yerra , Sri Nagarjun Batchu , Andrew Advani

Recent years have seen substantial scientific excitement in the role that the double-stranded DNA sensor and mediator of inflammation, stimulator of interferon genes (STING), plays in kidney disease. However, the STING pathway is not the sole regulator of inflammation, and STING has roles other than in inflammation. Here, elevated STING levels were observed in both human and mouse kidney disease, and the effects of STING deletion from kidney tubule cells, myeloid cells, and globally in experimental kidney disease were examined. Inflammatory gene up-regulation in tubule cells, induced by double-stranded DNA, was attenuated (but not negated) by STING knockout. Either myeloid or global knockout of STING marginally diminished fibroinflammatory gene up-regulation in mice with kidney injury caused by unilateral ureteral obstruction, whereas tubule cell knockout of STING unexpectedly augmented inflammatory gene up-regulation. Global knockout of STING similarly worsened diabetic kidney disease, likely due to heightened hyperglycemia. Antagonism of STING attenuated autophagy induction in human tubule cells, but not in human glomerular endothelial cells or podocytes. These findings serve as a counterweight to the enthusiasm that has recently emerged as to the roles of STING-mediated signaling in kidney disease. The actions of STING extend beyond its role in inflammation, and they are cell type dependent. STING may be a fine-tuner, but it is unlikely to be a prime mover, of inflammation in kidney disease.

近年来，人们对双链DNA传感器和炎症介质、干扰素基因刺激因子（STING）在肾脏疾病中的作用感到非常兴奋。然而，STING途径并不是炎症的唯一调节因子，STING在炎症之外还有其他作用。本研究在人类和小鼠肾脏疾病中均观察到STING水平升高，并研究了肾小管细胞、髓样细胞和所有实验性肾脏疾病中STING缺失的影响。在小管细胞中，由双链DNA诱导的炎症基因上调被STING敲除减弱（但未被否定）。在单侧输尿管梗阻引起的肾损伤小鼠中，髓系或整体敲除STING都能轻微降低纤维炎症基因的上调，而小管细胞敲除STING却意外地增强了炎症基因的上调。STING的整体敲除同样加重了糖尿病肾病，可能是由于高血糖升高。STING的拮抗作用减弱了人小管细胞的自噬诱导，但对人肾小球内皮细胞或足细胞没有作用。这些发现抵消了最近出现的关于sting介导的信号在肾脏疾病中的作用的热情。STING的作用超出了它在炎症中的作用，并且它们依赖于细胞类型。STING可能是一个微调器，但它不太可能是肾脏疾病炎症的原动力。

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引用次数: 0

Silencing Ubiquitin-Specific Peptidase 10 Alleviates Persistent Corneal Epithelial Defect in Mice 沉默USP10可减轻小鼠持续性角膜上皮缺陷。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2026-02-01 Epub Date: 2025-11-06 DOI: 10.1016/j.ajpath.2025.10.006

Arpan Banerjee , Mohammad Anjum Shaik , Christine Tilstra-Smith , Nileyma Castro , Jelissa Reynoso-Garcia , Michael E. Zuber , Audrey M. Bernstein

Persistent corneal epithelial defect is a condition in which the corneal epithelium fails to heal properly after injury, resulting in vision loss. Previous studies demonstrate that the deubiquitinase, ubiquitin-specific peptidase 10 (USP10), is a key regulator of wound healing and scarring in the cornea. Here, a highly modified in vivo self-delivering siRNA (sdRNA) targeting USP10 in a mouse model of persistent corneal epithelial defect was used. In this model, the corneal epithelium is scraped from the basement membrane and, although the wound initially closes, the epithelium re-opens at day 28, thereby modeling a persistent corneal defect. These studies revealed that one dose of USP10-targeting sdRNA after wounding prevented re-opening of the wound at day 28. Optical coherence tomography images, hematoxylin and eosin staining, and immunohistochemistry demonstrated improved corneal morphology and normal epithelial stratification of the regrown epithelium, with re-establishment of hemidesmosomes and reduced scarring and inflammation (CD45⁺ cells). Correspondingly, RNA sequencing of the regenerated corneal epithelium revealed that USP10 knockdown altered gene expression and pathways controlling tissue repair. Specifically, cell proliferation pathways were enhanced, whereas extracellular matrix, integrin, and immune cell signatures that lead to scar formation were reduced. The results demonstrate that a one-time application of in vivo sdRNA targeting USP10 is a novel method to prevent epithelial wound re-opening and subsequent scarring and inflammation and may be useful to promote regenerative healing in other tissues.

持续性角膜上皮缺损（PCED）是一种角膜上皮在损伤后不能正常愈合而导致视力丧失的疾病。先前的研究表明，去泛素酶USP10是角膜创面愈合和瘢痕形成的关键调节因子。在PCED小鼠模型中，我们使用了一种高度修饰的靶向USP10的体内自传递siRNA （sdRNA）。在该模型中，从基底膜上刮取角膜上皮，虽然伤口最初闭合，但上皮在第28天重新打开，从而形成了持续性角膜缺损。我们的研究显示，在受伤后1剂量usp10靶向sdRNA可防止伤口在第28天重新开放。光学相干断层扫描（OCT）图像、H&E染色和免疫组织化学显示，角膜形态改善，再生上皮上皮分层正常，半脂粒重建，瘢痕和炎症（CD45+细胞）减少。相应地，再生角膜上皮的RNA-Seq显示，USP10敲低改变了控制组织修复的基因表达和途径。具体来说，细胞增殖途径增强，而导致疤痕形成的细胞外基质、整合素和免疫细胞特征减少。我们的研究结果表明，一次性应用体内靶向USP10的sdRNA是一种防止上皮伤口重新开放和随后的疤痕和炎症的新方法，可能有助于促进其他组织的再生愈合。

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引用次数: 0

Inactivation of Atp7b Copper Transporter in Intestinal Epithelial Cells Is Associated with Altered Lipid Processing and Cell Growth Machinery Independent from Hepatic Copper Accumulation and Severity of Liver Histology 肠上皮细胞中Atp7b铜转运体的失活与脂质加工和细胞生长机制的改变有关，与肝铜积累和肝脏组织学的严重程度无关。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2026-02-01 Epub Date: 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.015

Amanda Caceres , Noreene M. Shibata , Christian D. Davalos-Gutierrez , Gaurav V. Sarode , Hisham Hussan , Margarida Bettencourt , Adriana Fontes , Hans Zischka , Svetlana Lutsenko , Marie C. Heffern , Valentina Medici

The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and brain, but little is known about the role of other organs expressing the ATP7B copper transporter on metabolic and ultrastructural changes characterizing WD. To examine the consequences of intestinal Atp7b inactivation in the absence of hepatic copper accumulation, a new mouse model (Atp7b^ΔIEC) characterized by enterocyte-specific Atp7b inactivation was generated. Atp7b^ΔIEC mice were compared with wild-type mice with the same genetic background (iWT). The Atp7b global knockout (Atp7b^–/–) model of WD on a C57Bl/6 background was previously generated and compared with its respective wild type (WT). Hepatic copper, lipid metabolism, liver and intestine histology, and electron microscopy were assessed over time up to 30 weeks of age. Although there was no evidence of intestine copper accumulation in Atp7b^ΔIEC mice, transcriptome analysis in Atp7b^ΔIEC mice revealed changes in genes involved in AMP-activated protein kinase signaling, fatty acid metabolism, and cell cycle both with partial overlap between the intestinal epithelial cells and the liver. Mitochondrial and other ultrastructural changes were observed in the intestinal epithelial cells of both Atp7b^–/– and Atp7b^ΔIEC mice. Intestine-specific Atp7b deficit affects systemic metabolic pathways and intestine morphology, and hepatic metabolic perturbations are associated with intestinal dysfunction, independently from hepatic copper accumulation, providing evidence that the WD phenotype is at least partially influenced by organ-specific ATP7B variants.

Wilson病（WD）的临床表现与铜在肝脏和大脑的积累有关，但对其他器官表达ATP7B铜转运体在WD代谢和超微结构变化中的作用知之甚少。为了研究在没有肝铜积累的情况下肠道Atp7b失活的后果，我们建立了一个以肠细胞特异性Atp7b失活为特征的新小鼠模型（Atp7bΔIEC）。将Atp7bΔIEC小鼠与具有相同遗传背景（iWT）的野生型小鼠进行比较。在C57Bl/6背景下，WD的Atp7b全基因敲除（Atp7b-/-）模型之前已被生成，并与各自的WT进行了比较。肝铜、脂质代谢、肝脏和肠道组织学以及电子显微镜在30周龄时进行了评估。虽然在Atp7bΔIEC小鼠中没有肠道铜积累的证据，但在Atp7bΔIEC小鼠中进行的转录组分析显示，参与AMPK信号、脂肪酸代谢和细胞周期的基因发生了变化，并且在肠上皮细胞和肝脏之间存在部分重叠。Atp7b-/-和Atp7bΔIEC小鼠肠上皮细胞均观察到线粒体和其他超微结构的改变。肠道特异性Atp7b缺陷影响全身代谢途径和肠道形态，肝脏代谢紊乱与肠道功能障碍相关，独立于肝铜积累，提供了WD表型至少部分受器官特异性Atp7b变异影响的证据。

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引用次数: 0