Yunxuan He, Danli Xiao, Hongfei Zhu, Chuxi Chen, Qiaoyuan Liu, Jinling Xie, Lvying Wei, Yueqi Dai, Yunshan Ning, Yan Li
{"title":"Notch信号通过促进巨噬细胞激活和促炎Th1/Th17反应加重幽门螺杆菌诱导的炎症","authors":"Yunxuan He, Danli Xiao, Hongfei Zhu, Chuxi Chen, Qiaoyuan Liu, Jinling Xie, Lvying Wei, Yueqi Dai, Yunshan Ning, Yan Li","doi":"10.1016/j.ajpath.2025.04.007","DOIUrl":null,"url":null,"abstract":"<div><div>The role of Notch signaling in regulating the immune response in infectious diseases has been extensively reported. However, its specific involvement in <em>Helicobacter pylori</em> infection is yet to be fully understood. In this study, <em>in vitro</em> analysis utilizing real-time quantitative PCR and Western blot revealed that <em>H. pylori</em> triggerred the activation of Notch signaling in murine bone marrow–derived macrophages (BMDMs) and co-cultured CD4<sup>+</sup> T cells, a process mediated by jagged-1 (Jag1). There was a reciprocal enhancement between Jag1-Notch signaling and NF-κB pathway in <em>H. pylori</em>–infected macrophages. Pretreatment with a Notch signaling inhibitor, DAPT, reduced the expression of inflammatory mediators in macrophages, modulated their phenotype, and inhibited Th1 differentiation. <em>In vivo</em>, after DAPT treatment in <em>H. pylori</em>–infected mice, the differentiation of Th1 and Th17 was decreased as indicated by flow cytometry. Hematoxylin and eosin staining revealed reduced gastric mucosa inflammation, and enzyme-linked immunosorbent assay results demonstrated decreased levels of serum inflammatory cytokines. The terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) results showed that DAPT treatment improved the apoptosis of gastric mucosal cells. Collectively, the findings indicate that Notch signaling is implicated in exacerbating <em>H. pylori–</em>induced inflammation by promoting macrophage activation and Th1/Th17 responses, highlighting its potential for alleviating the progression of <em>H. pylori</em>–related diseases.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 8","pages":"Pages 1428-1442"},"PeriodicalIF":4.7000,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Notch Signaling Aggravates Helicobacter pylori–Induced Inflammation by Promoting Macrophage Activation and Proinflammatory Th1/Th17 Responses\",\"authors\":\"Yunxuan He, Danli Xiao, Hongfei Zhu, Chuxi Chen, Qiaoyuan Liu, Jinling Xie, Lvying Wei, Yueqi Dai, Yunshan Ning, Yan Li\",\"doi\":\"10.1016/j.ajpath.2025.04.007\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The role of Notch signaling in regulating the immune response in infectious diseases has been extensively reported. However, its specific involvement in <em>Helicobacter pylori</em> infection is yet to be fully understood. In this study, <em>in vitro</em> analysis utilizing real-time quantitative PCR and Western blot revealed that <em>H. pylori</em> triggerred the activation of Notch signaling in murine bone marrow–derived macrophages (BMDMs) and co-cultured CD4<sup>+</sup> T cells, a process mediated by jagged-1 (Jag1). There was a reciprocal enhancement between Jag1-Notch signaling and NF-κB pathway in <em>H. pylori</em>–infected macrophages. Pretreatment with a Notch signaling inhibitor, DAPT, reduced the expression of inflammatory mediators in macrophages, modulated their phenotype, and inhibited Th1 differentiation. <em>In vivo</em>, after DAPT treatment in <em>H. pylori</em>–infected mice, the differentiation of Th1 and Th17 was decreased as indicated by flow cytometry. Hematoxylin and eosin staining revealed reduced gastric mucosa inflammation, and enzyme-linked immunosorbent assay results demonstrated decreased levels of serum inflammatory cytokines. The terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) results showed that DAPT treatment improved the apoptosis of gastric mucosal cells. Collectively, the findings indicate that Notch signaling is implicated in exacerbating <em>H. pylori–</em>induced inflammation by promoting macrophage activation and Th1/Th17 responses, highlighting its potential for alleviating the progression of <em>H. pylori</em>–related diseases.</div></div>\",\"PeriodicalId\":7623,\"journal\":{\"name\":\"American Journal of Pathology\",\"volume\":\"195 8\",\"pages\":\"Pages 1428-1442\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-04-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0002944025001488\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PATHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0002944025001488","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
Notch Signaling Aggravates Helicobacter pylori–Induced Inflammation by Promoting Macrophage Activation and Proinflammatory Th1/Th17 Responses
The role of Notch signaling in regulating the immune response in infectious diseases has been extensively reported. However, its specific involvement in Helicobacter pylori infection is yet to be fully understood. In this study, in vitro analysis utilizing real-time quantitative PCR and Western blot revealed that H. pylori triggerred the activation of Notch signaling in murine bone marrow–derived macrophages (BMDMs) and co-cultured CD4+ T cells, a process mediated by jagged-1 (Jag1). There was a reciprocal enhancement between Jag1-Notch signaling and NF-κB pathway in H. pylori–infected macrophages. Pretreatment with a Notch signaling inhibitor, DAPT, reduced the expression of inflammatory mediators in macrophages, modulated their phenotype, and inhibited Th1 differentiation. In vivo, after DAPT treatment in H. pylori–infected mice, the differentiation of Th1 and Th17 was decreased as indicated by flow cytometry. Hematoxylin and eosin staining revealed reduced gastric mucosa inflammation, and enzyme-linked immunosorbent assay results demonstrated decreased levels of serum inflammatory cytokines. The terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) results showed that DAPT treatment improved the apoptosis of gastric mucosal cells. Collectively, the findings indicate that Notch signaling is implicated in exacerbating H. pylori–induced inflammation by promoting macrophage activation and Th1/Th17 responses, highlighting its potential for alleviating the progression of H. pylori–related diseases.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.