American Journal of Pathology最新文献_第2页

Macrophage-Kruppel-Like Factor 6 Signaling Promotes Experimental Atherogenesis. 巨噬细胞-克虏伯样因子6信号传导促进实验性动脉粥样硬化。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-18 DOI: 10.1016/j.ajpath.2025.05.014

Hang Pong Ng, Atif Zafar, Rachel Diamond-Zaluski, Gun-Dong Kim, Kartik Bhat, Owen Meadows, Yashwant Pantra, E Ricky Chan, Jonathan D Smith, Ganapati H Mahabeleshwar

{"title":"Macrophage-Kruppel-Like Factor 6 Signaling Promotes Experimental Atherogenesis.","authors":"Hang Pong Ng, Atif Zafar, Rachel Diamond-Zaluski, Gun-Dong Kim, Kartik Bhat, Owen Meadows, Yashwant Pantra, E Ricky Chan, Jonathan D Smith, Ganapati H Mahabeleshwar","doi":"10.1016/j.ajpath.2025.05.014","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.05.014","url":null,"abstract":"A hallmark event in the development of atherosclerotic plaque is the accumulation of lipid-laden macrophages in the subendothelial layers of affected blood vessels. Macrophages are key players in all stages of atherogenesis, including plaque initiation, growth, and rupture, as well as healing of ruptured plaques. In this context, macrophages are the principal innate immune cells that modulate atherogenesis by engaging in various processes, such as inflammation, extracellular matrix degradation, phagocytosis, and efferocytosis. Here, this report shows that Kruppel-like factor 6 (KLF6) deficiency attenuates proinflammatory gene expression in macrophages and experimentally induced atherosclerotic plaque development. In vivo studies show that myeloid-KLF6 deficiency on Apoe-null background significantly curtails high-fat/high-cholesterol diet-induced atherosclerotic lesion formation and macrophage abundance in atherosclerotic plaques. Integrated transcriptomics and Gene Set Enrichment Analysis show that KLF6 deficiency significantly curtails a large number of tumor necrosis factor (TNF)-induced gene targets, TNF-induced interferon-γ response, interferon-α response, and inflammatory response signaling in macrophages. At the molecular level, KLF6 promotes IRF1 signaling to enhance TNF-induced proinflammatory gene expression in macrophages. Collectively, study results show that KLF6 promotes proinflammatory gene expression in macrophages and boosts experimentally induced atherosclerotic plaque formation in vivo.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hypoxia-Inducible Factor-1α-Induced Astrocytic D-Dopachrome Tautomerase Activates Microglial Inflammatory Response following Spinal Cord Injury. hif -1α诱导的星形细胞d -多巴胺自变性酶激活脊髓损伤后的小胶质细胞炎症反应。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-18 DOI: 10.1016/j.ajpath.2025.05.015

Aicheng Li, Mengdi Li, Si Xu, Li Niu, Shaolan Li, Yue Zhou, Zhilong Cao, Rixin Cai, Bingqiang He, Aisong Guo, Aihong Li, Honghua Song, Yongjun Wang, Yingjie Wang

{"title":"Hypoxia-Inducible Factor-1α-Induced Astrocytic D-Dopachrome Tautomerase Activates Microglial Inflammatory Response following Spinal Cord Injury.","authors":"Aicheng Li, Mengdi Li, Si Xu, Li Niu, Shaolan Li, Yue Zhou, Zhilong Cao, Rixin Cai, Bingqiang He, Aisong Guo, Aihong Li, Honghua Song, Yongjun Wang, Yingjie Wang","doi":"10.1016/j.ajpath.2025.05.015","DOIUrl":"10.1016/j.ajpath.2025.05.015","url":null,"abstract":"Spinal cord injury (SCI) often results in severe hypoxia and excessive activation of neuroinflammation, which aggravates neuropathology and neurologic dysfunction. D-dopachrome tautomerase (D-DT), the homolog of macrophage migration inhibitory factor, is a key proinflammatory mediator implicated in inflammatory diseases of multiple tissues. However, its relation with hypoxia and the potential impact on neuroinflammation following SCI remain elusive. Herein, the dynamic expression of D-DT, p65NF-κB, and the downstream proinflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6 at the lesion site was determined following SCI. D-DT inhibitor 4-(3-carboxyphenyl)-2,5pyridinedicarboxylic acid was applied to evaluate its effects on the inflammatory responses of the injured tissues. By using an in vitro cell model, the D-DT-mediated activation of microglia and the underlying regulatory mechanism were also investigated, showing that CD74/mitogen-activated protein kinase signaling was driven by D-DT to activate microglial inflammation. Analysis of rat D-DT promoter identified the binding element of hypoxia-inducible factor-1α. Hypoxia or dimethyloxallyl glycine stimulation of astrocytes was shown efficient in promoting the expression of hypoxia-inducible factor-1α and D-DT, whereas incubation of the microglia with the astrocytes' conditional medium was able to increase the production of tumor necrosis factor-α, IL-1β, and IL-6. Pharmacologic treatment of the subjects with 4-(3-carboxyphenyl)-2,5pyridinedicarboxylic acid or LW6 following SCI remarkably promoted the recovery of rat locomotor function. The results have presented a novel neuropathologic function of D-DT, which might be beneficial for development of potential drug targeting neuroinflammation.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Distinct Role of Dural and Leptomeningeal Macrophages in Maintaining Cerebrospinal Fluid Drainage to Meningeal Lymphatic Vessels. 硬脑膜和小脑膜巨噬细胞在维持脑脊液向脑膜淋巴管引流中的独特作用。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-18 DOI: 10.1016/j.ajpath.2025.05.017

Vikrim Lohat, Raffay Ilyas, Qing Wei, Darellynn Oo, Jingna Xue, Isabelle Horsman, Keith Keane, Matthew Stephens, Pierre-Yves von der Weid, Shan Liao

{"title":"Distinct Role of Dural and Leptomeningeal Macrophages in Maintaining Cerebrospinal Fluid Drainage to Meningeal Lymphatic Vessels.","authors":"Vikrim Lohat, Raffay Ilyas, Qing Wei, Darellynn Oo, Jingna Xue, Isabelle Horsman, Keith Keane, Matthew Stephens, Pierre-Yves von der Weid, Shan Liao","doi":"10.1016/j.ajpath.2025.05.017","DOIUrl":"10.1016/j.ajpath.2025.05.017","url":null,"abstract":"Cerebrospinal fluid (CSF) drains along the perivascular space, known as the glymphatic system, to the meninges, where meningeal lymphatic vessels (MLVs) remove toxic products with excess CSF from the brain. Macrophages are widely present in the leptomeninges and dura mater of meninges. However, whether leptomeningeal and dural macrophages play the same or distinct roles in maintaining optimal CSF drainage remains unclear. By intracisterna magna injection of clodronate liposomes, we observed a comprehensive depletion of leptomeningeal macrophages, a selective reduction in dural sinus-associated macrophages, a decreased density of MLVs, and disrupted CSF drainage. Further studies showed that macrophage depletion was associated with the infiltration of monocytes and the recovery of monocyte-derived macrophages. By day 14 after clodronate liposome, although both dural macrophages and MLVs had recovered, leptomeningeal macrophages and CSF drainage had not been restored. Furthermore, the study showed that i.p. injection of anti-colony-stimulating factor 1 receptor antibody selectively depleted macrophages in the dura mater but not in the leptomeninges, without affecting MLVs or CSF drainage. The study suggests that leptomeningeal macrophages, distinct from the dural macrophages, are essential for CSF drainage to the MLVs.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

This Month in AJP. 本月在AJP。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-13 DOI: 10.1016/j.ajpath.2025.06.001

引用次数: 0

Identification of Preclinical Biomarkers of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) versus MASLD and Increased Alcohol Intake and the Impact of Diet. MASLD与MetALD临床前生物标志物的鉴定及饮食的影响。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-12 DOI: 10.1016/j.ajpath.2025.05.013

Tyler C Gripshover, Rui S Treves, Josiah E Hardesty

{"title":"Identification of Preclinical Biomarkers of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) versus MASLD and Increased Alcohol Intake and the Impact of Diet.","authors":"Tyler C Gripshover, Rui S Treves, Josiah E Hardesty","doi":"10.1016/j.ajpath.2025.05.013","DOIUrl":"10.1016/j.ajpath.2025.05.013","url":null,"abstract":"Recent diagnostic advancements have characterized metabolic dysfunction-associated steatotic liver disease (MASLD) and increased alcohol intake (MetALD) if alcohol consumption is ≥ 20 or 30 g/d, females and males, respectively. Available treatments may affect dietary behavior or treat organ pathology but have limited effectiveness. There is a preclinical need for an animal model of MetALD that can assess concurrent diet and alcohol consumption on organ pathology to establish treatment strategies. Male, C57BL/6J mice were randomly assigned to six dietary groups for 13 weeks containing the following: ±chow diet (CD), ±high-fat diet (HFD), and water or 10% (v/v) ethanol. Glucose tolerance testing was performed at week 10. Physiological measures were assessed, and cecal 16S rRNA and liver mRNA sequencing were performed. HFD + ethanol (MetALD) mice had exacerbated dyslipidemia and gut dysbiosis relative to HFD + water (MASLD) mice. CD + HFD + ethanol mice had reduced glucagon-like peptide-1 relative to HFD + ethanol mice. MASLD and MetALD mice had altered transcription factor regulatory networks, which were altered with CD access. Kupffer cell markers are lower in HFD + ethanol mice relative to other groups. Diet and ethanol have distinct physiological effects in this MetALD model. Mice provided CD + HFD had worsened metabolic syndrome, but improved liver injury and microbiome diversity compared with HFD mice. Hepatic gene markers and microbiome changes of MASLD were identified. This preclinical model helps identify novel therapeutics to treat MASLD and MetALD.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Link between Alcohol Consumption and Kidney Injury. 饮酒与肾损伤之间的联系

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-11 DOI: 10.1016/j.ajpath.2025.05.011

Burhan Yokus, Luca Maccioni, Lihong Fu, György Haskó, Laura E Nagy, Bin Gao, Pal Pacher

{"title":"The Link between Alcohol Consumption and Kidney Injury.","authors":"Burhan Yokus, Luca Maccioni, Lihong Fu, György Haskó, Laura E Nagy, Bin Gao, Pal Pacher","doi":"10.1016/j.ajpath.2025.05.011","DOIUrl":"10.1016/j.ajpath.2025.05.011","url":null,"abstract":"Alcohol consumption contributes to systemic organ dysfunction, but its direct effect on kidney health is unclear. Epidemiologic studies have shown inconsistent findings due to a reliance on conventional markers, such as serum creatinine and blood urea nitrogen, which are insensitive to early chronic kidney disease and influenced by factors such as muscle mass, diet, and hydration status. Experimental studies have indicated that alcohol may directly exacerbate renal damage through mitochondrial dysfunction, oxidative stress, and inflammation. Furthermore, indirect effects from alcohol-induced altered intestinal permeability and microbiome, liver injury, microcirculatory/cardiac dysfunction and muscle damage may also facilitate kidney damage. Notably, alcohol-related liver disease can lead to hepatorenal syndrome, a severe type of kidney dysfunction driven by circulatory disturbances and systemic inflammation. This overview explores the adverse effects of alcohol misuse on kidney health and disease, emphasizing the need for comprehensive epidemiologic studies with more sensitive kidney injury biomarkers. It also highlights the importance of using clinically relevant preclinical models to clarify the underlying mechanisms of alcohol-related kidney injury and to enhance the understanding of its long-term clinical consequences.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Microbiota in Alcohol-Associated Organ Damage. 酒精相关器官损伤中的微生物群

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-11 DOI: 10.1016/j.ajpath.2025.05.012

Aenne Harberts, Bernd Schnabl

{"title":"Microbiota in Alcohol-Associated Organ Damage.","authors":"Aenne Harberts, Bernd Schnabl","doi":"10.1016/j.ajpath.2025.05.012","DOIUrl":"10.1016/j.ajpath.2025.05.012","url":null,"abstract":"Alcohol-associated organ damage is a major cause of morbidity and mortality worldwide, with the liver being the primarily affected organ. Emerging evidence highlights the gut microbiota as a key driver in alcohol-associated liver disease. Changes in the microbiota composition, microbial translocation, and a dysregulated immune response culminate in inflammation and tissue injury. Persistent liver injury eventually promotes disease progression from steatohepatitis to fibrosis and cirrhosis. In this review, an overview of microbiota alterations observed in patients with chronic alcohol consumption is provided and the mechanisms by which microbiota contributes to alcohol-associated damage across various organ systems are explored. Emphasis is placed on changes in the gut microbiota and its role in alcohol-associated liver disease, the disease condition with the most robust evidence linking microbiota-related changes to organ injury. Additionally, key areas where further research is needed to address unresolved questions are highlighted. Finally, emerging therapeutic strategies targeting the microbiota to treat alcohol use disorders and prevent alcohol-associated liver diseases are discussed.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Folliculin Deletion in the Mouse Kidney Results in Cystogenesis of the Loops of Henle via Aberrant TFEB Activation. 小鼠肾脏中卵泡蛋白缺失通过异常的TFEB激活导致Henle环的膀胱形成。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-09 DOI: 10.1016/j.ajpath.2025.05.010

Ola Shalaby, Tomoko Ohmori, Koichiro Miike, Shunsuke Tanigawa, Luh Ade Wilan Krisna, Alessia Calcagnì, Andrea Ballabio, Yoshiaki Kubota, Laura S Schmidt, W Marston Linehan, Takaaki Ito, Masaya Baba, Ryuichi Nishinakamura

{"title":"Folliculin Deletion in the Mouse Kidney Results in Cystogenesis of the Loops of Henle via Aberrant TFEB Activation.","authors":"Ola Shalaby, Tomoko Ohmori, Koichiro Miike, Shunsuke Tanigawa, Luh Ade Wilan Krisna, Alessia Calcagnì, Andrea Ballabio, Yoshiaki Kubota, Laura S Schmidt, W Marston Linehan, Takaaki Ito, Masaya Baba, Ryuichi Nishinakamura","doi":"10.1016/j.ajpath.2025.05.010","DOIUrl":"10.1016/j.ajpath.2025.05.010","url":null,"abstract":"The mammalian kidney contains numerous nephrons connected to the collecting ducts, and each nephron consists of a glomerulus, a proximal tubule, the loop of Henle (LoH), and a distal tubule. Folliculin (FLCN) is a causative gene for Birt-Hogg-Dubé syndrome, which is characterized by a variety of manifestations, including renal cysts and cancer. Although deletion of Flcn in the mouse collecting duct and distal nephron leads to cyst formation, its precise role in the entire nephron remains unclear. We report here that nephron-specific Flcn knockout mice exhibit cystogenesis along the entire nephron segments, most prominent in the LoH, preceded by an irregularly shaped lumen lined by enlarged epithelia. Single-cell RNA sequencing revealed many up-regulated genes, especially in the knockout LoH. These genes include those related to lysosomal activity and mammalian target of rapamycin complex 1 activation and are likely targets of transcription factor E3/transcription factor EB (TFEB). Although the double Flcn/Tfe3 knockout only ameliorates the glomerular cysts, the double Flcn/Tfeb knockout largely reverses most of the phenotypes along the entire nephron. Thus, Flcn deletion leads to cystogenesis via aberrant TFEB activation. Our findings show the essential role of the FLCN-TFEB signaling pathway in nephron development, particularly in LoH, and they shed light on the pathogenesis of Birt-Hogg-Dubé syndrome.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolic Dysfunction-Associated Steatotic Liver Disease in Patients and Mice with Wilson Disease. 肝豆状核变性患者和小鼠的代谢功能障碍相关脂肪变性肝病

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-09 DOI: 10.1016/j.ajpath.2025.05.009

Zixuan Wang, Qingyang Xu, Mengyu Wang, Qianqian Xiao, Yanhuang Xu, Xiaoying Wang, Yiwen Shi, Ruixu Yang, Jian-Gao Fan

{"title":"Metabolic Dysfunction-Associated Steatotic Liver Disease in Patients and Mice with Wilson Disease.","authors":"Zixuan Wang, Qingyang Xu, Mengyu Wang, Qianqian Xiao, Yanhuang Xu, Xiaoying Wang, Yiwen Shi, Ruixu Yang, Jian-Gao Fan","doi":"10.1016/j.ajpath.2025.05.009","DOIUrl":"10.1016/j.ajpath.2025.05.009","url":null,"abstract":"Wilson disease (WD) is a copper metabolism disorder caused by ATP7B gene mutations, and hepatic steatosis is not uncommon in WD. We therefore investigated the effects of ATP7B (ATPase copper-transporting beta) deficiency and/or a high-fat diet (HFD) on the development of steatohepatitis in mouse models and examined the relationship of hepatic steatosis with cardiometabolic factors in WD patients. A retrospective analysis of data was conducted on adults with WD. Atp7b gene knockout (KO) was achieved by CRISPR/Cas9 technology, followed by a comprehensive phenotypic analysis. An HFD was administered to induce steatohepatitis, allowing for analysis of lipid metabolism and hepatic injuries in KO mice subjected to overnutrition. Of 61 WD patients, 11.5% had evidence of hepatic steatosis, significantly linked to cardiometabolic factors. Although ATP7B KO mice under normal diets exhibited significant copper metabolism disorders without overt hepatic or neurologic injury, steatohepatitis was successfully induced in both wild-type and KO mice after 24 weeks of an HFD. Compared with a normal diet, an HFD resulted in markedly decreased hepatic copper levels with obvious liver injury in KO mice. Moreover, HFD-fed KO mice exhibited significantly higher severity of hepatic steatosis, inflammation, and fibrosis than wild-type control mice. Results suggest that hepatic steatosis in WD relates more to acquired metabolic dysfunction than excess copper accumulation, underscoring the influence of nutritional excess on WD phenotypes.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Early Endosome Disturbance and Endolysosomal Pathway Dysfunction in Duchenne Muscular Dystrophy. 杜氏肌营养不良的早期内溶酶体紊乱和内溶酶体通路功能障碍。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-09 DOI: 10.1016/j.ajpath.2025.05.007

Julie Chassagne, Nathalie Da Silva, Ines Akrouf, Bruno Cadot, Laura Julien, Ines Barthélémy, Stéphane Blot, Caroline Le Guiner, Mai Thao Bui, Norma B Romero, Jeanne Lainé, France Pietri-Rouxel, Pierre Meunier, Kamel Mamchaoui, Stéphanie Lorain, Marc Bitoun, Sofia Benkhelifa-Ziyyat

{"title":"Early Endosome Disturbance and Endolysosomal Pathway Dysfunction in Duchenne Muscular Dystrophy.","authors":"Julie Chassagne, Nathalie Da Silva, Ines Akrouf, Bruno Cadot, Laura Julien, Ines Barthélémy, Stéphane Blot, Caroline Le Guiner, Mai Thao Bui, Norma B Romero, Jeanne Lainé, France Pietri-Rouxel, Pierre Meunier, Kamel Mamchaoui, Stéphanie Lorain, Marc Bitoun, Sofia Benkhelifa-Ziyyat","doi":"10.1016/j.ajpath.2025.05.007","DOIUrl":"10.1016/j.ajpath.2025.05.007","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a lethal dystrophy characterized by the progressive loss of muscle fibers caused by mutations in DMD gene and absence of the dystrophin protein. Although autophagy and lysosome biogenesis defects have been described in DMD muscles, the endosomal pathway has never been studied. Here, it was shown that impaired lysosome formation is associated with altered acidification and reduced degradative function of the endolysosomal pathway in muscle cells derived from patients with DMD. The data demonstrated that early endosomes are increased in these cells as well as in muscle biopsies from patients with DMD and two animal models of DMD, mdx mice and golden retriever muscular dystrophy dogs. It was determined that these abnormalities are due to the lack of dystrophin per se and could be correlated with disease progression and severity. We further identified an abnormal up-regulation of the Rab5 GTPase protein, one key actor of early endosomal biogenesis and fusion, in the three DMD models, which may underlie the endosomal defects. Finally, we demonstrated that Rab5 knockdown in human DMD muscle cells as well as dystrophin restoration in golden retriever muscular dystrophy dogs normalize Rab5 expression levels and rescue endosomal abnormalities. This study unveils a defect in a pathway essential for muscle homeostasis and for the efficacy of DMD therapies.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0