American Journal of Pathology最新文献_第5页

From Single-Cancer to Pan-Cancer Prognosis 从单一癌症到泛癌症预后：具有鲁棒泛化能力的多模态深度学习生存分析框架。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-10 DOI: 10.1016/j.ajpath.2025.06.006

Binyu Zhang , Shichao Li , Junpeng Jian , Xiaoyu Ren , Ziqi Zhao , Limei Guo , Fei Su , Zhu Meng , Zhicheng Zhao

{"title":"From Single-Cancer to Pan-Cancer Prognosis","authors":"Binyu Zhang , Shichao Li , Junpeng Jian , Xiaoyu Ren , Ziqi Zhao , Limei Guo , Fei Su , Zhu Meng , Zhicheng Zhao","doi":"10.1016/j.ajpath.2025.06.006","DOIUrl":"10.1016/j.ajpath.2025.06.006","url":null,"abstract":"<div><div>Accurate prognosis represents a critical component in oncology research, enabling personalized treatment planning and optimized health care resource use. Although existing prognostic models demonstrate promising performance on restricted data sets, they remain constrained by two limitations: modality-specific architectural designs and cancer type–specific training paradigms that hinder cross-domain generalization. To address these challenges, the Unified Multimodal Pan-Cancer Survival Network (UMPSNet) was introduced, which integrated histopathology images, genomic expression profiles, and four metadata categories through structured text templates. UMPSNet used the optimal transport–based attention for multimodal feature alignment and a guided mixture of expert mechanisms to address cancer-type distribution shifts. Comprehensive evaluation across 3523 whole slide images (<em>n</em> = 2831) spanning five The Cancer Genome Atlas cohorts demonstrated superior predictive performance (mean concordance index = 0.725), surpassing meticulously designed single-cancer models. Notably, in zero-shot transfer evaluation involving 392 pancreatic adenocarcinoma whole slide images (<em>n</em> = 66) from Peking University Third Hospital, UMPSNet achieved a concordance index of 0.652 without parameter fine-tuning, demonstrating generalization capacity for previously unseen malignancies. Additionally, UMPSNet identified prognostic gene signatures that consistently overlapped with clinically detected mutations (<em>n</em> = 92) while revealing novel gene candidates, validating its clinical relevance and providing complementary insights for precision oncology. Thus, the UMPSNet framework established a new paradigm for multimodal survival analysis by overcoming data heterogeneity and domain shift challenges, thereby providing a clinically adaptable tool for pan-cancer prognostic prediction.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1869-1884"},"PeriodicalIF":3.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615837","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

Prostacyclin Assists in the Repair of Ruptured Amnions through the Proliferation and Migration of Amnion Mesenchymal Cells 前列环素通过羊膜间充质细胞的增殖和迁移帮助修复破裂的羊膜。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-09 DOI: 10.1016/j.ajpath.2025.06.002

Masahito Takakura , Yosuke Kawamura , Yusuke Ueda , Sunao Matsuzaka , Eriko Yasuda , Yu Matsuzaka , Asako Inohaya , Yoshitsugu Chigusa , Masaki Mandai , Shuh Narumiya , Koh-ichi Yuhki , Haruta Mogami

{"title":"Prostacyclin Assists in the Repair of Ruptured Amnions through the Proliferation and Migration of Amnion Mesenchymal Cells","authors":"Masahito Takakura , Yosuke Kawamura , Yusuke Ueda , Sunao Matsuzaka , Eriko Yasuda , Yu Matsuzaka , Asako Inohaya , Yoshitsugu Chigusa , Masaki Mandai , Shuh Narumiya , Koh-ichi Yuhki , Haruta Mogami","doi":"10.1016/j.ajpath.2025.06.002","DOIUrl":"10.1016/j.ajpath.2025.06.002","url":null,"abstract":"<div><div>Preterm prelabor rupture of membrane (pPROM) is a risk factor for preterm birth. However, spontaneous healing of ruptured fetal membranes is occasionally clinically observed. Prostaglandins are involved in the wound-healing process in various tissues. Here, the role of prostacyclin (PGI<sub>2</sub>) in the repair of fetal membranes was investigated in a mouse model. <em>Ptgs1</em>, <em>Ptgs2</em>, <em>Ptgis</em> mRNA, and PGI<sub>2</sub> were increased in the ruptured murine fetal membranes. Compared with the number of amnion mesenchymal cells at the intact site, the number of these cells at the rupture site was greater, and PGI<sub>2</sub> synthase was increased in the mesenchymal cells of the amnion. Repair of the ruptured amnion was compromised by treatment with a PGI<sub>2</sub> receptor (IP) antagonist, which decreased proliferation of the amnion mesenchymal cells. In contrast, an IP agonist partially restored repair of the amnion under the suppression of prostaglandin synthesis by a cyclooxygenase inhibitor. Compared with wild-type fetuses, IP-deficient fetuses exhibited impaired amnion repair, characterized by reduced proliferation of amnion mesenchymal cells observed at the rupture site. <em>In vitro</em>, the proliferation and migration of cultured human amnion mesenchymal cells were stimulated by an IP agonist and inhibited by an IP antagonist. These findings suggest that PGI<sub>2</sub> facilitates amnion repair by promoting the proliferation and migration of amnion mesenchymal cells.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1808-1821"},"PeriodicalIF":3.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615818","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 Substructure of the Endothelial Glycocalyx in Rat Aorta and Its Interaction with the Low-Density Lipoproteins 大鼠主动脉内皮糖萼亚结构及其与低密度脂蛋白的相互作用。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-09 DOI: 10.1016/j.ajpath.2025.06.005

Hongyan Kang , Guiqin Yan , Xiaoqian Lin , Yuwen Tian , Jiaxin Yin , Jiao Liu , Zhilan Deng , Jiaxin Guo , Jinyan Lu , Xubo Lin , Li Wang , Anqiang Sun , Xiaoyan Deng , Guixue Wang , Yubo Fan

{"title":"The Substructure of the Endothelial Glycocalyx in Rat Aorta and Its Interaction with the Low-Density Lipoproteins","authors":"Hongyan Kang , Guiqin Yan , Xiaoqian Lin , Yuwen Tian , Jiaxin Yin , Jiao Liu , Zhilan Deng , Jiaxin Guo , Jinyan Lu , Xubo Lin , Li Wang , Anqiang Sun , Xiaoyan Deng , Guixue Wang , Yubo Fan","doi":"10.1016/j.ajpath.2025.06.005","DOIUrl":"10.1016/j.ajpath.2025.06.005","url":null,"abstract":"<div><div>The influx and retention of the low-density lipoproteins (LDLs) in the subendothelial space are one of the early events of atherosclerosis. Initially, LDLs must traverse the endothelial glycocalyx, which is increasingly recognized for its critical role in preventing LDL penetration. However, the precise substructure of the glycocalyx and its working mechanism are still unknown. Herein, a well-preserved porous mesh-like glycocalyx at the luminal surface of rat aortas, demonstrated by high-pressure freezing/freeze substitution transmission electron microscopy, shows three subtypes. Mathematical modeling suggests the dense lower glycocalyx (0.2 to 2.9 μm) shows similar arrangement to that reported in microvessels, with the partition coefficient of LDL equaling 0. The other sparse higher one (0.8 to 17.3 μm) contributes to mechanotransduction. LDL affinity column chromatography combined with proteomic analysis, colocalization analysis, and cell transport experiments verifies, for the first time, that the glycocalyx does bind LDLs both <em>in vitro</em> and <em>in vivo</em>, but does not retain LDLs. Two-photon laser scanning microscopic imaging of mouse ear arterioles suggests that the electrostatic repulsion between LDL and glycocalyx is dominant relative to binding. These findings reveal the arrangement of dense lower glycocalyx together with its electrostatic repulsion toward LDLs works in preventing LDL penetration.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1936-1958"},"PeriodicalIF":3.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615819","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

Characterizing Kupffer Cell Production of CD5 Antigen-Like and Its Function on Regulating Migration of Natural Killer T Cells Kupffer细胞产生CD5L的特性及其在调节自然杀伤T细胞迁移中的作用

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-08 DOI: 10.1016/j.ajpath.2025.06.003

Handan Hong , Taojian Tu , Diala Alhousari , Lina He , Richa Aggarwal , Anketse Debebe , Chien-Yu Chen , Karam Ashouri , Anastasia Martynova , Christina Nakhoul , Ali Rastegarpour , Sina Baharlouei , Dai Peng , Eileen X. Stile , Meisam Razaviyayn , Sze-Chuan Suen , Enrique Cadenas , Houda Alachkar , Weiming Yuan , Keigo Machida , Bangyan L. Stiles

{"title":"Characterizing Kupffer Cell Production of CD5 Antigen-Like and Its Function on Regulating Migration of Natural Killer T Cells","authors":"Handan Hong , Taojian Tu , Diala Alhousari , Lina He , Richa Aggarwal , Anketse Debebe , Chien-Yu Chen , Karam Ashouri , Anastasia Martynova , Christina Nakhoul , Ali Rastegarpour , Sina Baharlouei , Dai Peng , Eileen X. Stile , Meisam Razaviyayn , Sze-Chuan Suen , Enrique Cadenas , Houda Alachkar , Weiming Yuan , Keigo Machida , Bangyan L. Stiles","doi":"10.1016/j.ajpath.2025.06.003","DOIUrl":"10.1016/j.ajpath.2025.06.003","url":null,"abstract":"<div><div>CD5 antigen-like (CD5L) is a multifunctional glycoprotein characterized for its role in the lipid metabolism, particularly within macrophages. In the liver, CD5L strongly correlates with liver injury. This study explored the role of CD5L on liver lipid accumulation and inflammatory response. CD5L promoted lipid uptake in hepatocytes and stellate cells. In multiple models of liver injury, expression of <em>Cd5l</em> was associated with that of <em>Clec4f</em>, a marker for liver macrophages, consistent with its role as a macrophage survival factor. Transwell assay was used to demonstrate a novel function of CD5L on promoting migration of natural killer T cells. This effect was independent of CD36, the characterized receptor of CD5L. This effect was also observed with liver macrophages, which are the cellular source for CD5L, and blocking CD5L attenuated natural killer T cell migration induced by liver macrophages. Finally, plasma levels of CD5L correlated with poor patient response to immune check point therapy that is dependent on response of T-cell populations. In addition, plasma CD5L levels correlated with levels of steatosis and severity of steatotic liver injury. Given the association between liver steatosis and poor response to immune checkpoint therapy, these data suggest that plasma CD5L levels may serve as a predictive biomarker for patient response to immune checkpoint therapy.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1839-1853"},"PeriodicalIF":3.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607161","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

Endothelial Cell Stimulator of Interferon Genes Regulates IL-6 Production and Is Required for Pathologic Cardiac Hypertrophy and Contractile Dysfunction in Experimental Heart Failure 内皮细胞STING调节il - 6的产生，是实验性心力衰竭病理性心肌肥大和收缩功能障碍所必需的。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-08 DOI: 10.1016/j.ajpath.2025.06.004

Erin Sanders , Kuljeet Kaur , Noah Wagner , Ramona Emig , Mark Aronovitz , Abraham L. Bayer , Brandon Theall , Albert Tai , Nina Martino , Miranda E. Good , Alejandro P. Adam , Robert Blanton , Pilar Alcaide

{"title":"Endothelial Cell Stimulator of Interferon Genes Regulates IL-6 Production and Is Required for Pathologic Cardiac Hypertrophy and Contractile Dysfunction in Experimental Heart Failure","authors":"Erin Sanders , Kuljeet Kaur , Noah Wagner , Ramona Emig , Mark Aronovitz , Abraham L. Bayer , Brandon Theall , Albert Tai , Nina Martino , Miranda E. Good , Alejandro P. Adam , Robert Blanton , Pilar Alcaide","doi":"10.1016/j.ajpath.2025.06.004","DOIUrl":"10.1016/j.ajpath.2025.06.004","url":null,"abstract":"<div><div>Capillary rarefaction and cardiomyocyte (CM) hypertrophy are hallmarks of the complex syndrome of heart failure (HF), a leading cause of hospitalization and death. Molecular signals within and between cellular components of the heart have emerged as central hubs that modulate cardiac pathophysiology. The stimulator of interferon genes (STING) was highly expressed in human and mouse cardiac endothelial cells (ECs) and was activated at the onset of HF. Global and inducible EC-specific STING<sup>−/−</sup> mice were used to demonstrate that EC STING is required for contractile dysfunction in an experimental model of HF induced by transverse aortic constriction, through the regulation of CM hypertrophy and capillary rarefaction. ECs from EC-STING<sup>−/−</sup> mice subjected to transverse aortic constriction were enriched in gene sets related to integrin and cell adhesion to extracellular matrix compared with controls. CellChat analysis of human cardiac cells from patients with nonischemic cardiomyopathy revealed EC-CM communication, and mechanistically, STING activation induced IL-6 secretion. Furthermore, EC-derived IL-6 was necessary to induce prohypertrophic gene expression in CMs in a STING-dependent manner. The study demonstrates a novel role for STING in ECs, contributing to hypertrophy and contractile dysfunction in experimental HF.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1788-1807"},"PeriodicalIF":3.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607162","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

DNA Methylation Dynamics in a Mouse Model of Retinitis Pigmentosa 色素性视网膜炎小鼠模型的DNA甲基化动力学。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-06-24 DOI: 10.1016/j.ajpath.2025.05.021

Lu Huang , Wai Lydia Tai , Kin-Sang Cho , Ajay Ashok , Maximilian Braun , Menglu Yang , Karen Chang , Anton Lennikov , Sarita Pooranawattanakul , Farris Elzaridi , Hio Tong Kam , Yizhen Tang , Qingfeng Li , Dong Feng Chen

{"title":"DNA Methylation Dynamics in a Mouse Model of Retinitis Pigmentosa","authors":"Lu Huang , Wai Lydia Tai , Kin-Sang Cho , Ajay Ashok , Maximilian Braun , Menglu Yang , Karen Chang , Anton Lennikov , Sarita Pooranawattanakul , Farris Elzaridi , Hio Tong Kam , Yizhen Tang , Qingfeng Li , Dong Feng Chen","doi":"10.1016/j.ajpath.2025.05.021","DOIUrl":"10.1016/j.ajpath.2025.05.021","url":null,"abstract":"<div><div>Retinitis pigmentosa (RP) is a group of sight-threatening genetic diseases characterized by progressive degeneration of photoreceptors, leading to severe vision loss from childhood to adulthood. With limited treatment options, understanding the molecular mechanisms underlying RP is crucial. Increased DNA methylation, especially in degenerating photoreceptors, is a contributing factor to retinal damage in RP. To exploit the molecular insights into methylation-driven pathways, this study investigated the DNA methylation patterns and their potential roles in photoreceptor degeneration in a mouse model of RP, specifically mice carrying a rhodopsin deficiency (<em>Rho</em><sup><em>–/–</em></sup>). Elevated levels of DNA methyltransferases (DNMTs) and DNA methylation were observed during photoreceptor degeneration. Importantly, weekly intravitreal injections of the pan DNMT inhibitor decitabine in <em>Rho</em><sup><em>–/–</em></sup> mice significantly improved photoreceptor morphology and visual function, as evidenced by electroretinogram, spectral-domain optical coherence tomography, and optomotor response-based visual behavior assays. Further histologic and immunohistochemical assessments revealed increased survival of cone photoreceptors and thicker outer nuclear layers in decitabine-treated mice compared with controls. Together, these findings revealed that the dynamics of DNA methylation correlate with photoreceptor degeneration. Inhibition of DNMTs mitigated the morphologic and functional impairments associated with the genetic defects in photoreceptors, suggesting that targeting DNA methylation could be a viable therapeutic strategy for neuroprotection in RP.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 9","pages":"Pages 1707-1718"},"PeriodicalIF":3.6,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504504","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

Activin A Prevents Hyperresponsiveness to Vascular Endothelial Growth Factor in Pathologic Blood Vessels by Perturbing the Trafficking of Activated Vascular Endothelial Growth Factor Receptor 2 激活素A通过干扰活化的VEGFR2的运输来防止病理血管中对VEGF的高反应性。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-06-24 DOI: 10.1016/j.ajpath.2025.05.022

Basma Baccouche , Maximilian McCann , Janani Rajasekar , Nguyễn Thị Thanh Nhàn , Kaori Yamada , Andrius Kazlauskas

{"title":"Activin A Prevents Hyperresponsiveness to Vascular Endothelial Growth Factor in Pathologic Blood Vessels by Perturbing the Trafficking of Activated Vascular Endothelial Growth Factor Receptor 2","authors":"Basma Baccouche , Maximilian McCann , Janani Rajasekar , Nguyễn Thị Thanh Nhàn , Kaori Yamada , Andrius Kazlauskas","doi":"10.1016/j.ajpath.2025.05.022","DOIUrl":"10.1016/j.ajpath.2025.05.022","url":null,"abstract":"<div><div>Although quality-of-life compromising afflictions, such as diabetic retinopathy (DR), are driven by vascular endothelial growth factor (VEGF), there is a growing appreciation that the concentration of VEGF is not the only influencer of vascular dysfunction within the retina. Herein, activin A (activin), a ligand of the transforming growth factor-β superfamily, attenuated VEGF-induced vascular endothelial–cadherin disorganization, pore formation, and permeability of primary human retinal endothelial cells. Efforts to further investigate the mechanism of this phenomenon revealed that activin reduced the expression of Rab11, which was required for the activin effect. The activin effect was not observed in cells with suppressed expression of the endosomally localized protein tyrosine phosphatase (PTP1b), whereas protein tyrosine phosphatases present on the plasma membrane were dispensable. Activin attenuated VEGF-mediated phosphorylation of VEGF receptor 2 at 30 minutes and longer post-stimulation time points. Together, these data support the concept that activin suppressed VEGF-induced barrier relaxation by perturbing trafficking of activated VEGF receptor 2. This activin-based suppression of responsiveness to VEGF was compromised in the endothelium of pathologic blood vessels from patients who developed end-stage proliferative DR. This defect rendered human retinal endothelial cell hyperresponsive to VEGF and was not observed in retinal vessels of diabetic mice, which do not develop the angiogenic forms of DR. These data provide novel insights into the pathogenesis of proliferative DR in patients.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 9","pages":"Pages 1736-1754"},"PeriodicalIF":3.6,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504503","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

From Disruption of Muscle Membrane to Muscle Membrane Repair 从肌膜破坏到肌膜修复

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-23 DOI: 10.1016/j.ajpath.2024.09.013

Shin'ichi Takeda

引用次数: 0

IL-6 trans-Signaling Regulates Neutrophilic Inflammation in Alcohol-Associated Hepatitis. 白细胞介素-6反式信号调控酒精相关性肝炎中性粒细胞炎症

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-23 DOI: 10.1016/j.ajpath.2025.05.023

Gaurav Sarode, Ming-Fo Hsu, Fawaz G Haj, Sergio Barace, Josepmaria Argemi, Mengfei Liu, Prisha Pandita, Sheng Cao, Vijay H Shah, Dorina Gui, Ramon Bataller, Vikrant Rachakonda

{"title":"IL-6 trans-Signaling Regulates Neutrophilic Inflammation in Alcohol-Associated Hepatitis.","authors":"Gaurav Sarode, Ming-Fo Hsu, Fawaz G Haj, Sergio Barace, Josepmaria Argemi, Mengfei Liu, Prisha Pandita, Sheng Cao, Vijay H Shah, Dorina Gui, Ramon Bataller, Vikrant Rachakonda","doi":"10.1016/j.ajpath.2025.05.023","DOIUrl":"10.1016/j.ajpath.2025.05.023","url":null,"abstract":"<p><p>Alcohol-associated hepatitis (AH) is a form of acute-on-chronic liver failure characterized by intrahepatic neutrophilic inflammation. In hepatocytes, IL-6 can signal through membrane-bound (classical signaling) or soluble (trans-signaling; TS) IL-6 receptors (IL-6Rs) to regulate liver injury responses. This study determined the role of IL-6TS in the pathophysiology of AH. Liver RNA sequencing in alcohol-related liver disease patients demonstrated declining IL-6R expression with increasing AH severity, and transforming growth factor (TGF)-β1 was the strongest negative regulator of IL-6R expression; however, STAT3-dependent gene expression was increased in severe AH. In vitro, HepG2 cells were exposed to TGF-β1 to inhibit IL-6R expression, followed by STAT3 activation with either IL-6 to stimulate classical signaling, or hyper-IL-6, a recombinant IL-6/IL-6R α peptide, to activate trans-signaling. Hyper-IL-6, but not IL-6, restored STAT3 activation in the face of suppressed IL-6R. RNA sequencing was performed on hyper-IL-6 stimulated cells, yielding a gene signature that identified a subset of AH patients with: i) enhanced IL-6TS activity, ii) increased intrahepatic neutrophilic infiltration, and iii) transcriptional enrichment of leukocyte migration pathways. Female mice treated with 10-day chronic-plus-binge ethanol exhibited enhanced STAT3 activation despite reduced hepatic IL-6R expression, leading to increased expression of neutrophilic activators, with colocalization of Ly6G<sup>+</sup> leukocytes and STAT3<sup>+</sup> hepatocytes. IL-6TS preserves hepatocyte STAT3-dependent gene expression and neutrophilic inflammation in AH.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493448","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

Retraction Notice to “Insulin-Induced Gene 2 Expression Is Associated with Breast Cancer Metastasis” [Am J Pathol 191 (2021) 385–395] “胰岛素诱导的基因2表达与乳腺癌转移相关”的撤回通知[J] .中华病理学杂志，1999,19 (2):385-395]

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-23 DOI: 10.1016/j.ajpath.2025.04.012

Ning Lu , Mei Zhang , Lu Lu , Yan-zhao Liu , Xiao-dong Liu , Hai-hong Zhang

引用次数: 0