American Journal of Pathology最新文献

{"title":"Deletion of Megalin in Kidney Tubular Epithelium Up-Regulates TGFβ1 Signaling, Aggravates Ischemia/Reperfusion Kidney Injury, and Accelerates the Progression to Chronic Kidney Disease","authors":"Qingtian Li ,&nbsp;Jeffery Li ,&nbsp;Li Tan ,&nbsp;Michael Holliday ,&nbsp;Emily Ji ,&nbsp;Sandhya Thomas ,&nbsp;Jizhong Cheng ,&nbsp;M.N.V. Ravi Kumar ,&nbsp;David Sheikh-Hamad","doi":"10.1016/j.ajpath.2025.11.011","DOIUrl":"10.1016/j.ajpath.2025.11.011","url":null,"abstract":"<div><div>Ischemic acute kidney injury may accelerate the progression to end-stage renal disease. Megalin has been shown to shuttle stanniocalcin (STC)-1 (which promotes mitochondrial antioxidant defenses) to the mitochondria through the retrograde-early endosomes–to–Golgi pathway; knockout of megalin in cultured cells has been reported to impair glycolysis and mitochondrial respiration. This study sought to determine kidney phenotype after ischemia/reperfusion (I/R) kidney injury in mice with tubular epithelium–specific deletion of megalin. Mice (on C57BL/6 background) with conditional tubular epithelium–specific knockout of megalin (<em>tLrp2KO</em>) and mice with combined conditional tubular epithelium–specific knockout of megalin and overexpression of <em>STC1</em> (<em>tLrp2KO</em>;<em>tSTC1O</em>) were subjected to ischemia (clamping of renal pedicles), followed by reperfusion for 1, 3, 10, 45, and 90 days. Serum creatinine was measured and kidneys were harvested for analysis. After I/R and compared with control mice, <em>tLrp2KO</em> mice displayed worse acute kidney injury, severe and persistent inflammation, diminished tubular epithelial cell proliferation, up-regulation of TGFβ1 signaling, fibrosis, and accelerated progression to chronic kidney disease. Kidney injury was not rescued in <em>tLrp2KO</em>;<em>tSTC1O</em> mice, consistent with megalin-dependent renal protection by STC1. Freshly isolated proximal tubule fragments from <em>tLrp2KO</em> mice or cultured proximal tubule epithelial cells with megalin knockout displayed activation of TGFβ1 signaling, consistent with modulation of TGFβ1 signaling by megalin. In conclusion, tubular epithelium–specific deletion of megalin aggravates I/R kidney injury, up-regulates TGFβ1 signaling, and accelerates chronic kidney disease progression.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 657-668"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888642","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}

{"title":"Specialized Pro-Resolving Mediators MaR1 and LXA4 Resolve Inflammation During Acute Chemical Lung Injury in the Absence of Neutrophils","authors":"Maureen E. Haynes,&nbsp;Vivienne Fang,&nbsp;Meital Gewirtz,&nbsp;David P. Sullivan,&nbsp;William A. Muller","doi":"10.1016/j.ajpath.2025.09.013","DOIUrl":"10.1016/j.ajpath.2025.09.013","url":null,"abstract":"<div><div>Gastric aspiration pneumonia involves chemical injury to the alveoli of the lungs with inflammation, tissue damage, and recruitment of polymorphonuclear leukocytes (PMNs). PMNs are also known to be involved in the production of specialized pro-resolving mediators (SPMs), small lipid molecules that contribute to the resolution of inflammation. This study aimed to identify target PMN-produced SPMs and interrogate their actions and potential use for therapeutic treatment after chemical injury. The data revealed that maresin 1 (MaR1), lipoxin A₄, and 18-HEPE are produced after chemical injury in the lungs, and that exogenous treatment with these SPMs reduces the acute influx of PMNs into the airspace. In a chemical lung injury model in which neutropenic mice all die within 48 hours, treatment with MaR1 or LXA₄ rescued survival of neutropenic mice to the levels of immunologically intact mice, and reduced CD11b expression, a proinflammatory marker, on recruited PMNs. Exogenous treatment with MaR1 or LXA₄ reduced the concentration of proinflammatory cytokines TNF⍺, IL6, and MCP-1 in the airspace at 24 hours after injury. These data show that exogenous treatment with MaR1 or LXA₄ ameliorates acute inflammation after chemical lung injury and contributes to survival of severe murine aspiration pneumonia in neutropenic animals. These data have implications for treatment of sterile lung injury in immunocompromised patients.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 359-368"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318084","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}

{"title":"YAP and TEAD Are Transcriptional Regulators of Neuroendocrine Differentiation and Growth in Carcinoid Cells","authors":"Jina Nanayakkara ,&nbsp;Xiaojing Yang ,&nbsp;Simona Damiani ,&nbsp;Tashifa Imtiaz ,&nbsp;Xiantao Wang ,&nbsp;Dimitrios G. Anastasakis ,&nbsp;Girish M. Shah ,&nbsp;Kathrin Tyryshkin ,&nbsp;Markus Hafner ,&nbsp;Xiaolong Yang ,&nbsp;Neil Renwick","doi":"10.1016/j.ajpath.2025.10.012","DOIUrl":"10.1016/j.ajpath.2025.10.012","url":null,"abstract":"<div><div>Molecular regulators of variably aggressive carcinoid tumors are unknown. Since carcinoids have low expression of Yes-associated protein (YAP), it was hypothesized that low YAP expression provides a molecular advantage to carcinoids by preventing YAP from binding its partner, TEA domain transcription factor (TEAD). To test this hypothesis, constitutively active YAP and a TEAD-binding defective form of YAP were overexpressed in lung (H727) and pancreatic (BON1) carcinoid cells. It was found that active YAP overexpression inhibited neuroendocrine markers, morphology, cell proliferation, and anchorage-independent cell growth, whereas TEAD-binding defective YAP recovered these features. Through integrated chromatin immunoprecipitation and RNA sequencing analyses, it was found that YAP-TEAD binding down-regulated neuroendocrine transcription factor genes and up-regulated select transforming growth factor (TGF-β) superfamily and Notch genes related to cell growth. It was concluded that low YAP expression permits neuroendocrine differentiation and growth in carcinoid cells by preventing YAP-TEAD binding and subsequent dysregulation of gene targets. These results identify unknown molecular mechanisms in carcinoid development that may apply to the broader family of neuroendocrine cancers.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 345-358"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581804","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}

{"title":"Cullin 2 Elevates the Warburg Effect to Accelerate the Development of Hypoxic Pulmonary Hypertension","authors":"Qiufen Xun,&nbsp;Qing Yang,&nbsp;Guofeng Zhu,&nbsp;Wei Wang","doi":"10.1016/j.ajpath.2025.11.001","DOIUrl":"10.1016/j.ajpath.2025.11.001","url":null,"abstract":"<div><div>Pulmonary arterial hypertension is a disease characterized by abnormally high pulmonary arterial blood pressures caused by a variety of heterogeneous diseases and different pathogenetic mechanisms. This study establishes a hypoxic pulmonary hypertension (HPH) mouse model, revealing cullin 2 (CUL2)'s critical role in disease pathogenesis. Hypoxia up-regulates CUL2 in HPH lungs, whereas CUL2 knockdown alleviates the Warburg effect, right ventricular dysfunction, and pulmonary fibrosis. <em>In vitro</em>, CUL2 depletion suppresses proliferation, adhesion, and tube formation in hypoxic pulmonary arterial endothelial cells. Mechanistically, CUL2 enhances glycolysis by up-regulating lactate dehydrogenase A (LDHA)/phosphofructokinase, liver type (PFKL), and their overexpression rescues CUL2-silencing effects. Furthermore, hypoxia-induced proline hydroxylase 2 (PHD2) down-regulation stabilizes hypoxia-inducible factor-1α (HIF-1α), which directly binds the <em>CUL2</em> promoter to enhance its expression. These findings unveil a novel PHD2/HIF-1α/CUL2 axis that promotes vascular remodeling via glycolysis, offering a potential therapeutic target for pulmonary arterial hypertension. In conclusion, this work demonstrated that under hypoxia condition, PHD2-mediated hydroxylation of HIF-1α was blocked and the expression of HIF-1α was elevated in HPH mice. High levels of HIF-1α elevated the transcription and expression of CUL2 and increased the Warburg effect, thereby accelerating HPH development.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 369-387"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627711","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}

{"title":"Improving Colorectal Cancer Screening and Risk Assessment through Predictive Modeling on Medical Images and Records","authors":"Shuai Jiang ,&nbsp;Christina Robinson ,&nbsp;Joseph Anderson ,&nbsp;William Hisey ,&nbsp;Lynn Butterly ,&nbsp;Arief Suriawinata ,&nbsp;Saeed Hassanpour","doi":"10.1016/j.ajpath.2025.09.016","DOIUrl":"10.1016/j.ajpath.2025.09.016","url":null,"abstract":"<div><div>Colonoscopy screening effectively identifies and removes polyps before they progress to colorectal cancer (CRC), but current follow-up guidelines rely primarily on histopathologic features, overlooking other important CRC risk factors. Variability in polyp characterization among pathologists also hinders consistent surveillance decisions. Advances in digital pathology and deep learning enable the integration of pathology slides and medical records for more accurate progression risk prediction. Using data from the New Hampshire Colonoscopy Registry, including longitudinal follow-up, a transformer-based model for histopathology image analysis was adapted to predict 5-year progression risk. Multi-modal fusion strategies were further explored to combine clinical records with deep learning–derived image features. Training the model to predict intermediate clinical variables improved 5-year progression risk prediction [area under the receiver-operating characteristic curve (AUC), 0.630] compared with direct prediction (AUC, 0.615; <em>P</em> = 0.013). Integrating whole-slide imaging–based model predictions with nonimaging features further improved performance (AUC, 0.672), significantly outperforming the nonimaging-only approach (AUC, 0.666; <em>P</em> = 0.002). These results highlight the value of integrating diverse data modalities with computational methods to enhance progression risk stratification.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 493-504"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318046","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}

{"title":"Periostin Deletion Reduces Corneal Opacity and the Infiltration of Immune Cells","authors":"Hyemin Seong ,&nbsp;Chieun Song ,&nbsp;Mingyo Kim ,&nbsp;Woong-Sun Yoo ,&nbsp;Mee-Young Choi ,&nbsp;Réka Dorottya Varga ,&nbsp;Yong-Ho Choe ,&nbsp;Bina Lee ,&nbsp;Seung Pil Yun ,&nbsp;Young-Sik Yoo ,&nbsp;Youngsub Eom ,&nbsp;Choun-Ki Joo ,&nbsp;Jinsung Yang ,&nbsp;Seong-Jae Kim","doi":"10.1016/j.ajpath.2025.09.007","DOIUrl":"10.1016/j.ajpath.2025.09.007","url":null,"abstract":"<div><div>Corneal opacity resulting from corneal injury is a leading cause of blindness. The interaction of extracellular matrix (ECM) proteins, cytokines, and immune cells induces corneal opacity after corneal injury. Periostin, which is secreted into the ECM, is involved in wound healing and is associated with immune cell infiltration. The function of periostin in corneal wound healing and in the development of corneal opacity was investigated. Wild-type (WT) and <em>Postn</em> knockout (KO) mice underwent central corneal incision. Periostin expression level was significantly increased after the incision in WT mice, correlating with higher levels of wound healing markers, such as fibronectin and α-smooth muscle actin, and increased corneal opacity. However, <em>Postn</em> KO mice showed reduced corneal opacity and immune cell infiltration, particularly from myeloid lineage cells after incision. In addition, pro-inflammatory cytokine levels (IL-1β, IL-6, and C1q) were not significantly changed in <em>Postn</em> KO mice. The results suggest that periostin deletion impairs corneal wound healing and reduces opacity by regulating cytokine expression and immune cell recruitment. The findings indicate that periostin can be a potential therapeutic target for reducing corneal opacity.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 550-561"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211317","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}

{"title":"Loss of Aquaporin-1 in Tumor Cells Fosters Intrahepatic Cholangiocarcinoma Progression","authors":"César I. Gaspari ,&nbsp;Carine Beaupere ,&nbsp;Seth Richard ,&nbsp;Estanislao Peixoto ,&nbsp;Bouchra Lekbaby ,&nbsp;Mirko Minini ,&nbsp;Branko Dubravcic ,&nbsp;Javier Vaquero ,&nbsp;Marie Vallette ,&nbsp;Ander Arbelaiz ,&nbsp;Marion Janona ,&nbsp;Corentin Louis ,&nbsp;Pauline Le Gall ,&nbsp;Cédric Coulouarn ,&nbsp;Julieta Marrone ,&nbsp;Juan E. Abrahante ,&nbsp;Raúl A. Marinelli ,&nbsp;Sergio A. Gradilone ,&nbsp;Laura Fouassier","doi":"10.1016/j.ajpath.2025.10.007","DOIUrl":"10.1016/j.ajpath.2025.10.007","url":null,"abstract":"<div><div>Aquaporin-1 (AQP1) is a water channel expressed by cholangiocytes described to modulate cell proliferation and invasion in several cancers. But the role of AQP1 in cholangiocarcinoma (CCA) remains unknown. The aim was to study the function of AQP1 in CCA. AQP1 expression was evaluated in 39 intrahepatic CCA (iCCA) specimens from transcriptomic data. AQP1-knockout in HuCCT1 iCCA cells was achieved by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9). Next-generation sequencing (RNA sequencing) was performed to study the consequences of AQP1 inhibition on cell phenotype. Epithelial-mesenchymal transition (EMT), cell migration and proliferation, and signaling pathways were evaluated by live-cell imaging system, quantitative RT-PCR, Western blot, and immunostaining. <em>In vivo</em> experiments were performed using a xenograft CCA model. In human iCCA, low AQP1 expression correlated with reduced overall survival. <em>In vivo</em>, CCA cells depleted for AQP1 displayed a higher tumorigenic potential than control cells. <em>In vitro,</em> RNA-sequencing analysis of AQP1-depleted CCA cells showed signatures of tumor progression, including EMT. Indeed, AQP1-depleted cells showed a cell dispersion phenotype, loss of the junction protein E-cadherin, and higher expression of vimentin and zinc finger E-box binding homeobox 1 (ZEB1), along with stemness traits. Functionally, loss of AQP1 is associated with increased cell migration and proliferation. Moreover, an activation of the insulin-like growth factor 2/insulin-like growth factor 1 receptor/insulin receptor pathway was found in AQP1-depleted CCA cells. The data suggest that AQP1 acts as a tumor suppressor in iCCA.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 428-444"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476755","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}

{"title":"PathViT Model for Automated Disease Classification from Skeletal Muscle Histopathology","authors":"Taymaz Akan ,&nbsp;Sait Alp ,&nbsp;Richa Aishwarya ,&nbsp;Diensn G. Xing ,&nbsp;Destyn Dicharry ,&nbsp;Md. Shenuarin Bhuiyan ,&nbsp;Mohammad Alfrad Nobel Bhuiyan","doi":"10.1016/j.ajpath.2025.10.009","DOIUrl":"10.1016/j.ajpath.2025.10.009","url":null,"abstract":"<div><div>Analyzing skeletal muscle pathology from histological images is labor intensive (requiring manual cell counting, segmentation, and thresholding), time consuming, and prone to inter- and intrauser variability, influencing the accuracy and consistency of diagnoses. To address these difficulties, PathViT, a transformer-based deep-learning model, was designed to automatically distinguish between healthy and diseased muscle fibers, with the aims of reducing human intervention, minimizing subjectivity and variability, and significantly decreasing analysis time compared to conventional manual methods. Skeletal muscle pathology is characterized by changes in myofiber cross-sectional area, increased central nuclei, and structural disruptions in sarcomeres. To investigate these changes in myofiber size, wheat germ agglutinin staining and digital histopathology of skeletal muscle (quadriceps, gastrocnemius, tibialis anterior, extensor digitorum longus, and soleus) was utilized to classify diseased tissue [amyotrophic lateral sclerosis (<em>SOD1∗G93A</em>) and type 1 diabetes (Akita)] versus nondiseased controls. The performance of PathViT in distinguishing diseased versus nondiseased muscle fibers was compared with that of state-of-the-art deep-learning models. PathViT classified healthy and diseased muscle fibers with 96% accuracy, outperforming the other models. This approach enhanced scalability and diagnostic accuracy and decreased variability, making PathViT a potentially powerful biomedical research and clinical tool.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 505-514"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476779","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}

{"title":"Quantitative 3D Imaging of Mouse and Human Intrahepatic Bile Ducts in Homeostasis and Liver Injury","authors":"Hannah R. Hrncir ,&nbsp;Brianna Goodloe ,&nbsp;Sergei Bombin ,&nbsp;Siyang J. Sun ,&nbsp;Zelin Zhang ,&nbsp;Anant Madabhushi ,&nbsp;Adam D. Gracz","doi":"10.1016/j.ajpath.2025.10.008","DOIUrl":"10.1016/j.ajpath.2025.10.008","url":null,"abstract":"<div><div>Intrahepatic bile ducts (IHBDs) form a complex hierarchical network essential for liver function. The remodeling and expansion of this network during ductular reaction (DR) are hallmarks of liver disease that can be key indicators of disease severity. Conventional histology fails to capture the full extent of IHBD structural changes after injury due to the complex three-dimensional (3D) organization of the IHBD network that limits understanding of DR, especially in human tissue. A major barrier to leveraging 3D imaging as a diagnostic tool is the absence of standardized pipelines for IHBD imaging and analysis. This work establishes a robust 3D IHBD imaging and analysis workflow, applying it to both mouse and human liver tissues. This pipeline enables quantification of tissue and individual duct (“segment”) level features and identifies features of invasive and noninvasive DR. In mouse models, we uncover regional phenotypes, including IHBD diverticula-like structures after duct blockage and the formation of anastomosed clusters after hepatocellular injury. Finally, this 3D imaging and analysis workflow is applied to quantify IHBD networks in human liver tissue. This work deepens our understanding of IHBD architecture in homeostasis and injury, laying the groundwork for advanced phenotyping of IHBD morphologies in mice and humans with relevance to next-generation experimental and diagnostic approaches to liver disease.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 445-459"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996377","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}

{"title":"Targeting RORγ to Boost Regulatory T cells and Ameliorate Diabetic Retinopathy in Mice","authors":"Devy Deliyanti,&nbsp;Varaporn Suphapimol,&nbsp;Phoebe Ang,&nbsp;Abhirup Jayasimhan,&nbsp;Jennifer L. Wilkinson-Berka","doi":"10.1016/j.ajpath.2025.09.006","DOIUrl":"10.1016/j.ajpath.2025.09.006","url":null,"abstract":"<div><div>Diabetic retinopathy, a leading cause of blindness, features damage to the retinal vasculature, where T-cell–mediated inflammation is increasingly recognized as an important contributor. Retinoic acid receptor-related orphan receptor gamma (RORγ) plays a key role in regulating the balance between anti-inflammatory regulatory T cells (Tregs) expressing the transcription factor Foxp3 and proinflammatory Th17 cells. It was hypothesized that inhibiting RORγ with SR2211, targeting both RORγ and its isoform RORγt, increases Tregs and reduces Th17 cells, resulting in reduced inflammation and vasculopathy in a streptozotocin-induced model of diabetic retinopathy. Mice expressing Foxp3 as a red fluorescent protein were treated with SR2211 for 26 weeks of diabetes, and comparisons made to diabetic mice administered vehicle and non-diabetic control mice. In blood and lymphoid tissues of diabetic mice, treatment with SR2211 restored the number of Tregs and reduced Th17 cells to the levels of diabetic mice + vehicle. In the retina of diabetic mice, treatment with SR2211 increased Tregs and reduced the activation of microglia cells, the expression of proinflammatory factors including IL-17A, IL-6 and tumor necrosis factor, vascular leakage, vascular endothelial growth factor, and acellular capillaries, compared with diabetic mice + vehicle. These findings indicate the ability of RORγ/RORγt inhibition to modulate specific T-cell responses and suppress microglia activation to reduce inflammation and vascular damage in diabetic retinopathy.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 562-574"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211330","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}