Xiaolin Ma , Xuan Zhao , Yulong Yang , Jinjin Yan , Xiaoyan Shi , Hongfei Wu , Yarong Liu , Min Dai
{"title":"Paeonol inhibits NETs-mediated foam cell inflammation through the CitH3/NLRP3/caspase-1 signaling pathway in atherosclerosis","authors":"Xiaolin Ma , Xuan Zhao , Yulong Yang , Jinjin Yan , Xiaoyan Shi , Hongfei Wu , Yarong Liu , Min Dai","doi":"10.1016/j.intimp.2025.114340","DOIUrl":null,"url":null,"abstract":"<div><div>Atherosclerosis is a chronic inflammatory disease characterized by lipid streaks, which are produced by aggregates of lipid-rich foam cells. Foam cells intensify atherosclerosis by secreting a range of inflammatory mediators. Neutrophil extracellular traps produced by activated neutrophils, which are abundantly present in lipid-accumulating plaques. However, the relationship between neutrophil extracellular traps and foam cells inflammation is still unclear. Paeonol is well known for its anti-inflammatory effects in atherosclerosis. Nevertheless, the exact pharmacological mechanisms by which paeonol affects atherosclerosis are not fully understood which require further investigation. The purpose of this study is to investigate the effects of paeonol on the neutrophil extracellular traps' formation and foam cell inflammation caused by neutrophil extracellular traps, and to explore the potential mechanisms. A high-fat diet was administered to ApoE<sup>−/−</sup> mice for a period of 12 weeks to induce an atherosclerosis model. Our findings demonstrated that paeonol notably suppressed the advancement of atherosclerosis in ApoE<sup>−/−</sup> mice, curtailed the formation of neutrophil extracellular traps, and lowered inflammatory factor levels within the plaque. <em>In vitro</em> studies have shown that neutrophil extracellular traps could enhance the inflammation in foam cells. CitH3 played a role in the cellular communication between neutrophil extracellular traps and foam cells. Concurrently, NLRP3 acted as a key receptor in the inflammation mediated by this interaction. Paeonol is capable of regulating NE, thereby affecting the formation of neutrophil extracellular traps. Most notably, the foam cell inflammation caused by neutrophil extracellular traps was significantly mitigated by the inclusion of paeonol. Our findings suggested that paeonol inhibited foam cell inflammation which induced by neutrophil extracellular traps through the CitH3/NLRP3/caspase-1 signaling pathway, shedding new lights on its anti-atherosclerotic pharmacological mechanism.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"151 ","pages":"Article 114340"},"PeriodicalIF":4.8000,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International immunopharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1567576925003303","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Atherosclerosis is a chronic inflammatory disease characterized by lipid streaks, which are produced by aggregates of lipid-rich foam cells. Foam cells intensify atherosclerosis by secreting a range of inflammatory mediators. Neutrophil extracellular traps produced by activated neutrophils, which are abundantly present in lipid-accumulating plaques. However, the relationship between neutrophil extracellular traps and foam cells inflammation is still unclear. Paeonol is well known for its anti-inflammatory effects in atherosclerosis. Nevertheless, the exact pharmacological mechanisms by which paeonol affects atherosclerosis are not fully understood which require further investigation. The purpose of this study is to investigate the effects of paeonol on the neutrophil extracellular traps' formation and foam cell inflammation caused by neutrophil extracellular traps, and to explore the potential mechanisms. A high-fat diet was administered to ApoE−/− mice for a period of 12 weeks to induce an atherosclerosis model. Our findings demonstrated that paeonol notably suppressed the advancement of atherosclerosis in ApoE−/− mice, curtailed the formation of neutrophil extracellular traps, and lowered inflammatory factor levels within the plaque. In vitro studies have shown that neutrophil extracellular traps could enhance the inflammation in foam cells. CitH3 played a role in the cellular communication between neutrophil extracellular traps and foam cells. Concurrently, NLRP3 acted as a key receptor in the inflammation mediated by this interaction. Paeonol is capable of regulating NE, thereby affecting the formation of neutrophil extracellular traps. Most notably, the foam cell inflammation caused by neutrophil extracellular traps was significantly mitigated by the inclusion of paeonol. Our findings suggested that paeonol inhibited foam cell inflammation which induced by neutrophil extracellular traps through the CitH3/NLRP3/caspase-1 signaling pathway, shedding new lights on its anti-atherosclerotic pharmacological mechanism.
期刊介绍:
International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome.
The subject material appropriate for submission includes:
• Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders.
• Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state.
• Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses.
• Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action.
• Agents that activate genes or modify transcription and translation within the immune response.
• Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active.
• Production, function and regulation of cytokines and their receptors.
• Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.