American Journal of Pathology最新文献_第9页

SCG2 Transcriptionally Activated by SP1 Promotes Nasal Epithelial Cell Proliferation and Epithelial Mesenchymal Transition 被SP1转录激活的SCG2促进鼻上皮细胞增殖和上皮间质转化。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-12 DOI: 10.1016/j.ajpath.2025.07.016

Jiabin Zhan, Quan Qiu, Zhengling Chen, Xin Wei, Xi Chen, Jing Zheng

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a tendency to recur and a poor prognosis. Epithelial mesenchymal transition (EMT) and proliferation of nasal epithelial cells (NECs) play an important role in CRSwNP development. Secretogranin II (SCG2) is reported to be an EMT-related gene, but its role in CRSwNP has not been reported. In this study, human NECs were cultured in an air–liquid interface culture system and stimulated with IL-13 to maintain or promote the CRSwNP state. EMT-associated protein expression levels were examined by real-time quantitative PCR and Western blot. Dual luciferase, chromatin immunoprecipitation, and co-immunoprecipitation experiments were used to validate the regulatory relationship between SP1, SCG2, and ubiquitin-1 (UBQLN1). The nuclear translocation of Snail was examined by immunofluorescence assay. The results showed that the expression levels of SP1, SCG2, and UBQLN1 were all up-regulated in CRSwNP tissues. SCG2 knockdown inhibited EMT and proliferation of human NECs. Mechanistically, SP1 promoted the proliferation and EMT of human NECs by transcriptionally increasing SCG2 expression. SCG2 activated the AKT serine/threonine kinase (AKT)/glycogen synthase kinase-3 beta (GSK-3β)/Snail family transcriptional repressor 1 (Snail) pathway and promoted Snail nuclear translocation via UBQLN1. In short, SCG2, which is transcriptionally up-regulated by SP1, promotes the proliferation and EMT of human NECs by activating the AKT/GSK-3β/Snail pathway through binding to UBQLN1.

慢性鼻窦炎伴鼻息肉（CRSwNP）具有复发倾向和预后差的特点，上皮间充质转化（EMT）和鼻上皮细胞（NECs）的增殖在CRSwNP的发展中起重要作用。据报道，分泌granin II （SCG2）是emt相关基因，但其在CRSwNP中的作用尚未报道。本研究将人NECs培养在气液界面培养系统（ALI）中，并通过IL-13刺激维持或促进CRSwNP状态。采用qRT-PCR和western blot检测emt相关蛋白的表达水平。采用双荧光素酶、ChIP和Co-IP实验验证SP1、SCG2和UBQLN1之间的调控关系。采用免疫荧光法检测蜗牛的核易位。结果显示，SP1、SCG2和UBQLN1在CRSwNP组织中的表达水平均上调。SCG2敲低抑制EMT和人NECs的增殖。在机制上，SP1通过转录增加SCG2的表达促进了人NECs的增殖和EMT。SCG2激活AKT/GSK-3β/Snail通路，并通过UBQLN1促进Snail核易位。简而言之，SP1转录上调的SCG2通过与UBQLN1结合激活AKT/GSK-3β/Snail通路，从而促进人NECs的增殖和EMT。

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引用次数: 0

Growth Differentiation Factor 11 Attenuates Photoaging through Ferroptosis Pathway in SZ95 Sebocytes 生长分化因子11在SZ95脂细胞中通过铁下垂途径减弱光老化。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-12 DOI: 10.1016/j.ajpath.2025.07.015

Ying Liu , Jingran Zeng , Xueyi Liu , Youyou Qin , Yingbo Zhang , Christos C. Zouboulis , Zhibo Xiao

Sebaceous glands synthesize and secrete sebum, forming a protective barrier on the skin. However, prolonged exposure to UV radiation leads to glandular atrophy and reduced sebum production. This study investigated the impact of UVB irradiation on sebocyte function and demonstrated that growth differentiation factor (GDF)-11 can attenuate UVB-induced damage. The findings indicate that cumulative UVB irradiation induces photoaging in sebocytes, characterized by impaired cellular function and up-regulation of cellular senescence markers, along with reduced GDF11 expression. Notably, GDF11 overexpression alleviated these adverse effects. Apoptosis assays revealed that photoaged sebaceous gland cells exhibited resistance to apoptosis. Transmission electron microscopy further identified features indicative of ferroptosis. UVB exposure led to increased intracellular reactive oxygen species, decreased expression of the ferroptosis-related protein glutathione peroxidase (GPX)-4, and elevated levels of long-chain fatty acid–CoA ligase (ACSL)-4 and nuclear receptor coactivator (NCOA)-4. Further experiments confirmed that GDF11 overexpression increased the percentage of apoptotic cells and down-regulated GPX4 and ACSL4 expression, whereas GDF11 knockdown produced the opposite effects. These results suggest that GDF11 mitigates sebocyte photoaging via the ferroptosis pathway and highlight its potential as a therapeutic target.

皮脂腺合成和分泌皮脂，在皮肤上形成一个保护屏障。然而，长时间暴露在紫外线（UV）辐射下会导致腺体萎缩和皮脂分泌减少。本研究探讨了UVB照射对脂细胞功能的影响，并证明生长分化因子11 （GDF11）可以减轻UVB诱导的损伤。我们的研究结果表明，累积的UVB照射可诱导皮脂细胞光老化，其特征是细胞功能受损，细胞衰老标志物上调，同时GDF11表达降低。值得注意的是，GDF11过表达减轻了这些不良反应。细胞凋亡实验显示，光老化皮脂腺细胞表现出细胞凋亡的抗性。透射电镜进一步确定了铁下垂的特征。UVB暴露导致细胞内活性氧（ROS）增加，铁中毒相关蛋白GPX4表达降低，ACSL4和NCOA4水平升高。进一步的实验证实，GDF11过表达增加了凋亡细胞的比例，下调了GPX4和ACSL4的表达，而GDF11敲低则产生相反的作用。这些结果表明GDF11通过铁下垂途径减轻了脂细胞的光作用，并突出了其作为治疗靶点的潜力。

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引用次数: 0

Single-Cell and Spatial Transcriptomics–Based Research Reveals Association Between M2a Macrophages and Tumor Spread through Air Spaces in Lung Adenocarcinoma 基于单细胞和空间转录组学的研究揭示了肺腺癌中M2a巨噬细胞与肿瘤通过空气空间扩散之间的关联。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-12 DOI: 10.1016/j.ajpath.2025.07.017

Yun Ding , Han Zhang , Hui Wen , Shutong Zhao , Jiuzhen Li , Xin Liu , Kai Wang , Yangyun Huang , Meilin Xu , Daqiang Sun

Tumor spread through air spaces (STAS) is a pathologic feature of lung cancer with prognostic significance, and it is also a cutting-edge hotspot in the clinical field of lung cancer. However, the current mechanisms underlying the occurrence and colonization of STAS in lung adenocarcinoma (LADC) remain unclear. Single-cell RNA sequencing combined with Digital Spatial Profiling spatial transcriptomics sequencing, which aligns well with the spatial characteristics of STAS and the tumor microenvironment, was innovatively used in this research to explore the mechanisms by which specific types of tumor-associated macrophages influence the occurrence and development of STAS in LADC. This study suggests that M2a macrophages are associated with STAS in LADC and patient prognosis. M2a macrophages may enhance STAS in LADC by promoting β-catenin signaling through the chemokine (C-C motif) ligand 17/CCR4 axis. Therefore, targeting tumor-associated macrophages could be a beneficial precision treatment strategy for patients with STAS-positive LADC. In addition, the tumor microenvironment exhibits significant spatial heterogeneity, and its spatial characteristics should be fully considered when studying tumors.

肿瘤通过空气间隙扩散（STAS）是肺癌具有预后意义的病理特征，也是肺癌临床领域的前沿热点。然而，目前尚不清楚STAS在肺腺癌（LADC）中发生和定植的机制。本研究创新性地利用与STAS和肿瘤微环境（TME）的空间特征非常吻合的单细胞RNA测序与Digital Spatial Profiling空间转录组测序相结合的方法，探索特定类型的肿瘤相关巨噬细胞（tumor-associated macrophages, tam）影响LADC中STAS发生发展的机制。本研究提示M2a巨噬细胞与LADC中的STAS及患者预后相关。M2a巨噬细胞可能通过CCL17-CCR4轴促进β-catenin信号通路，从而增强LADC的STAS。因此，靶向tam可能是stas阳性LADC患者的一种有益的精准治疗策略。此外，TME具有显著的空间异质性，在研究肿瘤时应充分考虑其空间特征。

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引用次数: 0

Dehydroepiandrosterone Prevents Collagen Loss by Regulating HIF-1α Expression and Mitophagy in Hypoxic Human Scleral Fibroblasts 脱氢表雄酮通过调节缺氧人巩膜成纤维细胞HIF-1α表达和线粒体自噬防止胶原流失。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-12 DOI: 10.1016/j.ajpath.2025.07.018

Qi Zhang , Jing Chen , Haichun Li , Jing Yang , Jieyong Huang , Bingqian Liu , Shida Chen , Ping Lian , Lin Lu , Xiujuan Zhao

Myopia progression and its associated complications, which can lead to vision impairment, primarily result from persistent abnormal elongation of the eye's axial length. The previous metabonomic analysis of intraocular fluids suggested intraocular hormones may play a role in high myopia pathogenesis. In this study, significantly reduced concentrations of dehydroepiandrosterone (DHEA) were discovered in the vitreous humor of high myopia eyes. Additionally, DHEA levels in retina tissues of myopic guinea pigs were significantly decreased, further linking intraocular DHEA depletion to myopia-related tissue changes. Recent research has established scleral hypoxia as a fundamental mechanism underlying myopia development, with scleral fibroblasts serving as key functional cells in this process. Thus, this study investigated the effects of DHEA on human scleral fibroblasts under hypoxic conditions to generate novel insights for myopia prevention and treatment. The findings demonstrated that DHEA down-regulates hypoxia-inducible factor 1α (HIF-1α) expression and reduces collagen loss under hypoxic conditions. Additionally, DHEA reversed the decreased cell proliferation observed in human scleral fibroblasts in vitro. These effects appear to be mediated through changes in mitochondrial dynamics and regulation of BNIP3L-mediated mitophagy induced by DHEA under hypoxia. The results suggest DHEA represents a promising novel therapeutic strategy for preventing myopia development.

近视进展及其相关并发症可导致视力损害，主要是由眼轴长度持续异常延长引起的。以往的眼内液代谢组学分析提示眼内激素可能在高度近视的发病机制中起作用。本研究发现，高度近视眼玻璃体内脱氢表雄酮（DHEA）浓度显著降低。此外，近视豚鼠视网膜组织中的脱氢表雄酮水平显著降低，进一步将眼内脱氢表雄酮消耗与近视相关的组织变化联系起来。最近的研究发现，巩膜缺氧是近视发生的基本机制，巩膜成纤维细胞在这一过程中起关键作用。因此，本研究探讨了DHEA在缺氧条件下对人巩膜成纤维细胞（hsf）的影响，为近视的预防和治疗提供新的见解。结果表明，脱氢表雄酮可下调缺氧诱导因子1α (HIF-1α)的表达，减少缺氧条件下胶原蛋白的损失。此外，脱氢表雄酮逆转了体外hsf中观察到的细胞增殖下降。这些作用似乎是通过缺氧条件下DHEA诱导的线粒体动力学变化和bnip3l介导的线粒体自噬调节介导的。结果表明脱氢表雄酮代表了一种有希望的预防近视发展的新治疗策略。

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引用次数: 0

From Theory to Practice 从理论到实践：腹膜假性黏液瘤研究综述及其对未来治疗的意义。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-11 DOI: 10.1016/j.ajpath.2025.08.005

Han Gao , Hongli Wang , Xiufeng Li , Fulei Zhang , Yiru Ba , Jiatong Zhao , Chengwei He , Shuzi Xin , Xiaohui Liu , Guowei Liang

Pseudomyxoma peritonei (PMP) is a rare disease characterized by symptoms such as mucinous ascites and omental cake, typically arising from a perforated epithelial tumor of the appendix. Because of its rarity, non-specific histologic characteristics, and slow progression, its pathogenesis and optimal treatment remain subjects of debate. PMP is still a challenging and enigmatic condition. Increasing global attention is being directed toward understanding its pathogenesis and establishing standard treatment approaches. PMP and mucin are inextricably linked. This article highlighted the important role of mucin in the disease's pathogenesis. It also discussed several potential therapeutic strategies for eliminating mucin in PMP. Tumor development and metastasis involve a series of steps that include the interaction between the tumor and the host-derived stromal environment, which promotes angiogenesis and activation of inflammatory cells. Inflammatory cytokines and chemokines play a crucial role in the progression and development of PMP. The microbiome and specific microorganisms may directly influence tumor development, progression, and responses to certain therapies in PMP. Thus, the article summarized the interactions among bacteria, the immune system, and mucin in PMP, focusing on the mechanisms that related to abnormal mucin and tumor growth. This review critically examined the existing literature on the clinical features, pathologic processes, and treatment options in PMP, aiming to guide future research toward identifying novel therapeutic targets and gut-related disease biomarkers.

腹膜假性粘液瘤（PMP）是一种罕见的疾病，其症状为粘液性腹水和大网膜饼，通常由阑尾穿孔的上皮肿瘤引起。由于其罕见性、非特异性的组织学特征和缓慢的进展，其发病机制和最佳治疗仍然是争论的主题。PMP仍然是一个具有挑战性和神秘的条件。越来越多的全球关注的方向是了解其发病机制和建立标准的治疗方法。PMP和粘蛋白有着千丝万缕的联系。本文强调粘蛋白在本病发病机制中的重要作用。本文还讨论了几种消除PMP中粘蛋白的潜在治疗策略。肿瘤的发展和转移涉及一系列步骤，包括肿瘤与宿主源性基质环境的相互作用，促进血管生成和炎症细胞的激活。炎症因子和趋化因子在PMP的进展和发展中起着至关重要的作用。微生物组和特定微生物可能直接影响PMP的肿瘤发生、进展和对某些治疗的反应。因此，本文综述了PMP中细菌、免疫系统和粘蛋白的相互作用，重点探讨了粘蛋白异常与肿瘤生长的相关机制。本文对PMP的临床特征、病理过程和治疗方案进行了综述，旨在指导未来的研究，以确定新的治疗靶点和肠道相关疾病的生物标志物。

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引用次数: 0

Laminin Receptors in Peripheral Tissues 外周组织层粘连蛋白受体——敲除小鼠分析揭示的功能。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-11 DOI: 10.1016/j.ajpath.2025.08.007

Wanling Xuan , Yao Yao

Laminin, by interacting with its receptors (mainly integrins and dystroglycan), exerts a variety of important functions in multiple organs. Loss-of-function studies have described the essential roles of laminin receptors in both physiological and pathologic conditions. This review summarizes the pathology and loss-of-function phenotypes of laminin receptors, including integrin-α3, integrin-α6, integrin-α7, integrin-β1, integrin-β4, and dystroglycan, focusing on the skin, kidney, skeletal muscle, peripheral nervous system, mammary gland, lung, and heart. To explore the functional redundancy/compensation among different laminin receptors, the phenotypes of compound knockout mice are compared with that of single mutants. Next, key signaling pathways downstream of each laminin receptor are summarized and compared. In addition, key questions in the field and future directions are also discussed. The aim of this review was to provide a synthetic review on loss-of-function studies of laminin receptors and foster the formation and testing of new hypotheses in the field.

层粘连蛋白通过与其受体（主要是整合素和糖酐）相互作用，在多个器官中发挥多种重要功能。功能丧失研究已经证明了层粘连蛋白受体在生理和病理条件下的重要作用。本文综述了层粘连蛋白受体的病理和功能丧失表型，包括整合素-α3、-α6、-α7、-β1、-β4和糖酐异常，重点介绍了皮肤、肾脏、骨骼肌、周围神经系统、乳腺、肺和心脏。为了探索不同层粘连蛋白受体之间的功能冗余/补偿，我们将复合敲除小鼠的表型与单突变小鼠的表型进行了比较。接下来，总结和比较各层粘连蛋白受体下游的关键信号通路。此外，还对该领域的关键问题和未来发展方向进行了讨论。本文旨在对层粘连蛋白受体功能丧失的研究进行综述，并促进该领域新假设的形成和检验。

引用次数: 0

The Role of Extracellular Vesicle–Derived miRNA in the Atherosclerotic Burden 细胞外囊泡来源的miRNA在动脉粥样硬化负担中的作用。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-11 DOI: 10.1016/j.ajpath.2025.08.006

Alessandra S. Rizzuto , Isabella Fichtner , Stefano Carugo , Annalisa Radeghieri , Chiara Macchi , Massimiliano Ruscica

In the context of atheroma-related sequelae, the role of extracellular vesicles (EVs) continues to spike interest. Their ability to traffic molecular cargo between cells highlights their role in intercellular communication, and consequently their involvement in mediating molecular events at the basis of physiological and pathologic processes. EVs encapsulate miRNAs within their lumen, shielding them from circulating ribonucleases, which would otherwise catalyze their degradation. However, there is an ongoing debate regarding the implication of miRNA contained within EVs in modulating biological activities on a molecular level. Therefore, the aim of the present review is to discuss the role of EV-derived miRNA, focusing on their implication in molecular mechanisms underlying atheroma formation. EVs of endothelial origin can regulate monocyte activation by transferring miR-10a that targets components of the inflammatory pathway. Tail vein administration of EVs derived from endothelial cells enriched in miR-34c-5p markedly reduces atherosclerosis progression. In patients with stable coronary artery disease, elevated levels of miR-126 and miR-199a in circulating EVs are significantly associated with a reduced incidence of major adverse cardiovascular event rate. These nanoparticles, released by all cells into most biological fluids, hold promise as a liquid biopsy tool as their circulating patterns and cargo can reflect the onset and severity of cardiovascular diseases.

在动脉粥样硬化相关后遗症的背景下，细胞外囊泡（EVs）的作用继续引起人们的兴趣。它们在细胞间运输分子货物的能力突出了它们在细胞间通讯中的作用，因此它们在生理和病理过程的基础上参与介导分子事件。电动汽车将mirna封装在其腔内，保护它们不受循环核糖核酸酶的影响，否则核糖核酸酶会催化它们的降解。然而，关于ev中含有的microRNA （miR）在分子水平上调节生物活性的意义，一直存在争议。因此，本综述的目的是讨论ev衍生的miR的作用，重点讨论它们在动脉粥样硬化形成的分子机制中的意义。内皮来源的EVs可以通过传递靶向炎症通路成分的miR-10a来调节单核细胞活化。尾静脉给药来源于富集miR-34c-5p的内皮细胞的ev可显著降低动脉粥样硬化的进展。在稳定性冠状动脉疾病患者中，循环ev中miR-126和miR-199a水平升高与主要不良心血管事件发生率降低显著相关。这些由所有细胞释放到大多数生物液体中的纳米颗粒有望作为液体活检工具，因为它们的循环模式和货物可以反映心血管疾病的发病和严重程度。

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引用次数: 0

This Month in AJP 本月在AJP。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-09 DOI: 10.1016/j.ajpath.2025.09.001

引用次数: 0

Aldehyde Dehydrogenase 2 Deficiency Impairs Liver Progenitor Cell Proliferation in Alcohol-Fed Mice 醛脱氢酶2缺乏损害酒精喂养小鼠肝祖细胞增殖。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-03 DOI: 10.1016/j.ajpath.2025.08.004

Peng Xiao , Siting Yang , Shenghua Bi , Yawen Hao , Feiyu Zhang , Lin Ru , Tao Liu , Shengying Qian , Qiuhong Zai , Ningning Ma , Junqi Niu , Yong He , Yanhang Gao

Aldehyde dehydrogenase 2 (ALDH2) is a critical enzyme involved in the detoxification of acetaldehyde. Although numerous studies have demonstrated the significance of ALDH2 in alcohol-associated liver disease, its role in alcohol-induced activation of liver progenitor cells (LPCs) has not been thoroughly investigated. Proteomic analysis of serum samples from patients with either normal ALDH2 genotype or ALDH2 mutation following alcohol consumption revealed that ALDH2 deficiency may suppress LPC proliferation. To test this hypothesis, Aldh2 knockout (Aldh2KO) mice were generated and fed a 3,5-diethoxycarbonyl1,4-dihydrocollidine–supplemented diet along with 10% ethanol in drinking water. A significant inhibition of LPC proliferation was observed in Aldh2KO mice after alcohol exposure, as indicated by reduced numbers of pan-cytokeratin (PanCK)– and Ki-67–positive cells in the liver. Bulk RNA sequencing revealed that differentially expressed genes (DEGs) in 3,5-diethoxycarbonyl1,4-dihydrocollidine plus ethanol-fed Aldh2KO mice were enriched in pathways related to inflammation (up-regulated DEGs) and cell cycle suppression (down-regulated DEGs) based on Reactome pathway analysis compared with wild-type mice. Mechanistically, alcohol exposure in Aldh2KO mice led to reduced LPC proliferation, likely mediated by enhanced hepatic pyroptosis and inflammatory responses. In conclusion, these findings suggest that ALDH2 deficiency appears to impair LPC proliferation in alcohol-associated liver disease, highlighting the critical role of ALDH2 in liver regeneration following alcohol-induced injury.

醛脱氢酶2 （ALDH2）是参与乙醛解毒的关键酶。尽管大量研究已经证明ALDH2在酒精相关性肝病（ALD）中的重要意义，但其在酒精诱导的肝祖细胞（LPCs）活化中的作用尚未得到充分研究。对ALDH2基因型正常或ALDH2基因型突变患者的血清样本进行蛋白质组学分析显示，ALDH2缺乏可能抑制LPC增殖。为了验证这一假设，我们培育了Aldh2敲除（Aldh2KO）小鼠，并给它们喂食添加了3,5-二氧羰基1,4-二氢碰撞碱（DDC）的饮食，同时在饮用水中添加10%的乙醇。酒精暴露后，Aldh2KO小鼠的LPC增殖明显受到抑制，肝脏中panck和ki67阳性细胞数量减少。大量RNA测序（RNA-seq）显示，与野生型（WT）小鼠相比，基于Reactome通路分析，DDC加乙醇喂养的Aldh2KO小鼠中差异表达基因（DEGs）在炎症（DEGs上调）和细胞周期抑制（DEGs下调）相关通路中富集。在机制上，酒精暴露在Aldh2KO小鼠中导致LPC增殖减少，可能是由肝焦亡和炎症反应增强介导的。总之，这些发现表明，ALDH2缺乏似乎会损害ALD中LPC的增殖，突出了ALDH2在酒精诱导损伤后肝脏再生中的关键作用。

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引用次数: 0

Novel Perineural Pathways and the Dynamics of SIV-Infected Macrophage Trafficking Out of the Central Nervous System 新的神经周围通路和猴免疫缺陷病毒感染的巨噬细胞运输出中枢神经系统的动力学。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-02 DOI: 10.1016/j.ajpath.2025.07.014

Zoey K. Wallis , Yingshan Wei , Lily M. Ceraso , Cecily C. Midkiff , Addison Q. Amadeck , Yiwei Wang , Andrew D. Miller , Robert V. Blair , Kenneth C. Williams

A challenge to eradicate HIV is the central nervous system (CNS) reservoir and unknown mechanisms-pathways by which infected macrophages can exit. We used intracisternal injection of superparamagnetic iron oxide nanoparticles (SPIONs), some of which had different internal immune fluorescence to define perineural pathways of SPION⁺ macrophage traffic in SIV-infected animals with AIDS, on antiretroviral therapy (ART) and with ART interruption. SPION⁺ macrophages are identified in central (spinal cord and cranial nerves) and peripheral (dorsal root ganglia) sites. In noninfected animals, SPION⁺ macrophages traffic out normally. With SIV infection, SPION⁺ macrophages accumulate in the CNS, and there are decreased numbers that traffic out. SIV-RNA and SIV-glycoprotein 41 (gp41) SPION⁺ macrophages are found in cranial nerves and dorsal root ganglion that are significantly reduced, but not eliminated, with ART. Using SPIONs with two different internal fluorescences, injected early and late after SIV infection, we find AIDS animals have greater numbers of early injected SPION⁺ macrophages within cranial nerves, consistent with reduced traffic late. With ART, there are greater numbers of late and dual (early and late) labeled SPION⁺ macrophages in the periphery, that return to levels found in AIDS animals following ART interruption. These findings reveal a novel pathway by which CNS macrophages can redistribute virus from the CNS to the periphery that persists despite ART.

根除艾滋病毒的一个挑战是中枢神经系统的储存库和未知的机制-被感染的巨噬细胞可以退出的途径。我们采用腹腔注射超顺磁性氧化铁纳米颗粒（SPION），其中一些具有不同的内部免疫荧光，以确定SIV感染的艾滋病动物、抗逆转录病毒治疗和抗逆转录病毒治疗中断时SPION+巨噬细胞运输的神经周围通路。SPION+巨噬细胞见于中枢（脊髓和脑神经）和外周（背根神经节）部位。在未感染动物中，SPION+巨噬细胞正常输出。SIV感染时，SPION+巨噬细胞在中枢神经系统内积聚，流出的数量减少。在脑神经和DRG中发现SIV- RNA和gp41 SPION+巨噬细胞，ART显著减少，但未消除。通过在SIV感染早期和晚期注射两种不同内部荧光的SPION，我们发现艾滋病动物早期在脑神经内注射的SPION+巨噬细胞数量更多，与后期交通量减少一致。在抗逆转录病毒治疗中，外周有更多的晚期和双（早期和晚期）标记SPION+巨噬细胞，它们在抗逆转录病毒治疗中断后恢复到艾滋病动物的水平。这些发现揭示了一种新的途径，通过这种途径，中枢神经系统巨噬细胞可以将病毒从中枢神经系统重新分配到外周，尽管抗逆转录病毒疗法仍然存在。

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引用次数: 0