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}
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}
Benliang Wei , Anhong Li , Guofa Zhao , Rongfang Liu , Peng Liu , Xu Zhang , Fangchao Zhao , Shujun Li , Xinyue Zhang , Xuguang Zhang
{"title":"Single-Cell Sequencing Reveals the Palmitoylation Landscape in Lung Adenocarcinoma and Identifies ABHD17C as a Novel Biomarker","authors":"Benliang Wei , Anhong Li , Guofa Zhao , Rongfang Liu , Peng Liu , Xu Zhang , Fangchao Zhao , Shujun Li , Xinyue Zhang , Xuguang Zhang","doi":"10.1016/j.ajpath.2025.05.024","DOIUrl":"10.1016/j.ajpath.2025.05.024","url":null,"abstract":"<div><div>Protein S-palmitoylation, a reversible posttranslational modification, is crucial for tumor progression. However, the palmitoylation landscape in tumor cells and its variability within different tumor cell populations remain underexplored. This study was designed to analyze protein palmitoylation using 23 palmitoyl-acyltransferases and 7 de-palmitoyl-acyltransferases. Copy number variation, pseudotime, enrichment, and cell-cell communication analyses were used to explore heterogeneity among epithelial cells in lung adenocarcinoma. Palmitoylation levels were elevated in normal epithelial cells, whereas depalmitoylation predominated in tumor-derived cells. As clinical stage advanced, palmitoylation declined and depalmitoylation increased. A C4 epithelial subtype associated with epithelial-to-mesenchymal transition and angiogenesis, marked by low palmitoylation and high depalmitoylation, was identified. This subtype, located at the end of the tumorigenic trajectory, showed intense communication with fibroblasts and endothelial cells but minimal interaction with immune cells, indicating enhanced invasiveness and immune evasion. <em>ABHD17C</em>, a key marker of the C4 subtype, regulated tumor cell proliferation, and its knockdown reduced growth and increased apoptosis. A C4 epithelial subtype linked to lung adenocarcinoma metastasis was identified and <em>ABHD17C</em> emerged as a potential biomarker and therapeutic target.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 9","pages":"Pages 1575-1587"},"PeriodicalIF":3.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526082","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}
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}
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}
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}
Ning Lu , Mei Zhang , Lu Lu , Yan-zhao Liu , Xiao-dong Liu , Hai-hong Zhang
{"title":"Retraction Notice to “Insulin-Induced Gene 2 Expression Is Associated with Breast Cancer Metastasis” [Am J Pathol 191 (2021) 385–395]","authors":"Ning Lu , Mei Zhang , Lu Lu , Yan-zhao Liu , Xiao-dong Liu , Hai-hong Zhang","doi":"10.1016/j.ajpath.2025.04.012","DOIUrl":"10.1016/j.ajpath.2025.04.012","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Page 1358"},"PeriodicalIF":4.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144472428","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}
Anabela Djurovic-Topalovic, Natalie G Horgan, Jessica S Fortin
{"title":"Updates on Tau-Related Drug Targets and Potential Disease-Modifying Therapies for Alzheimer's Disease.","authors":"Anabela Djurovic-Topalovic, Natalie G Horgan, Jessica S Fortin","doi":"10.1016/j.ajpath.2025.05.020","DOIUrl":"10.1016/j.ajpath.2025.05.020","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a chronic, multifactorial neurodegenerative disease affecting a large proportion of the elderly population with detrimental psychological and socioeconomic impacts. This review starts with a brief overview of the molecular aspects of AD. It aims to provide recent updates on several potential protein targets studied as valid therapeutic approaches such as Bassoon protein, triggering receptor expressed on myeloid cells 2 (TREM2), phosphorylated tau (chimeric molecules DEPTAC and PhosTAC), O-GlcNAcase (OGA), and misfolded protein seeds. This review emphasizes the importance of pursuing a multifaceted approach to diversify and synergize the current AD pharmacotherapy.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339820","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}
Houman Homayoun, Michael R DeChellis-Marks, Julia Kofler, Gabriella Fricklas, Amanda M Gleixner, Fang-Cheng Yeh, David Lacomis, Charleen T Chu, Christopher J Donnelly
{"title":"Novel Kinesin Family Member 1A Variants Linked to Atypical Parkinsonism Elicit Altered Neuronal Transactive Response DNA Binding Protein 43 kDa Interactions and Dendritic Atrophy.","authors":"Houman Homayoun, Michael R DeChellis-Marks, Julia Kofler, Gabriella Fricklas, Amanda M Gleixner, Fang-Cheng Yeh, David Lacomis, Charleen T Chu, Christopher J Donnelly","doi":"10.1016/j.ajpath.2025.05.018","DOIUrl":"10.1016/j.ajpath.2025.05.018","url":null,"abstract":"<p><p>Analysis of induced pluripotent stem cell (iPSC)-derived neurons from the son of a father-son pair with novel familial variants of uncertain significance in kinesin family member 1A (KIF1A) [c.408C>G (p.Asp136Glu); c.3914G>A (p.Arg1305His)] reveal pathologic features of altered transactive response DNA binding protein 43 kDa (TDP-43) localization, interactions, and stunted dendritic arbors. Both patients developed spasticity and parkinsonism in their mid-60s, with the father dying at age 70 years. There was impaired putamenal dopamine uptake with preserved uptake in the caudate nuclei, and decreased anisotropy by tractography in multiple motor pathways. Given shared transcriptional mechanisms of hindbrain and spinal cord developmental patterning among neurons of the motor circuitry, iPSC-derived motor neurons from fibroblasts donated by the son were generated to investigate the impact of KIF1A mutations on TDP-43 subcellular localization, biochemical interactions of endogenous wild type and mutant KIF1A and endogenous TDP-43, and the pathologic impact of these KIF1A variants on dendritic arborization using Sholl analysis. Neuropathologic assessment of the father, who shared the same KIF1A variants, revealed tauopathy and TDP-43 proteinopathy throughout the brainstem. Quantitative imaging of patient iPSC neurons identified TDP-43 mislocalization to the soma and dendritic atrophy. The KIF1A mutant also elicited decreased biochemical interactions of both itself and TDP-43 with a spectrum of known TDP-43-associated proteins. These data suggest that this novel KIF1A mutant mediates altered TDP-43 interactions, stunting of the synaptic architecture, and clinical phenotypes coincident with neurodegenerative movement disorders.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339819","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}