慢性牙周炎通过肝脏IL-6/STAT3/Hepcidin信号通路对全身铁稳态的影响

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-02-06 DOI:10.1016/j.intimp.2024.114002

Jinglan Zhang , Xuan Chen , Dingming Huang , Xuelian Tan

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引用次数: 0

摘要

背景与目的：慢性根尖牙周炎（CAP）是一种以牙龈卟啉单胞菌（P. gingivalis）为主要病原体的细菌感染引起的口腔炎症性疾病，具有全身性影响，可能影响包括肝脏在内的远端器官。肝脏通过hepcidin在铁代谢和免疫中起关键作用。本研究旨在探讨P. gingivalis诱导的CAP对肝脏和全身铁代谢的影响，重点关注IL-6/STAT3信号通路在肝脏hepcidin合成中的作用。方法：采用牙龈卟啉单胞菌致牙髓室感染的方法建立小鼠CAP模型。ELISA法检测血清IL-6、铁蛋白、hepcidin水平。采用高通量测序分析肝脏基因表达，免疫组织化学荧光染色验证肝组织蛋白表达。结果：CAP使血清铁、铁蛋白、IL-6水平发生显著变化。基因本体（GO）和京都基因与基因组百科全书（KEGG）通路分析显示JAK/STAT信号通路和急性期反应等通路富集，基因集富集分析（GSEA）也显示IL-6/JAK/STAT3信号通路活化。免疫荧光证实IL-6、p-STAT3和hepcidin表达增加。静态治疗可减轻这些水平，减轻cap诱导的炎症和铁调节作用。结论：P. gingivalis诱导的CAP可引发全身性炎症，并通过IL-6/STAT3信号通路破坏铁代谢，可能影响肝功能。靶向这一途径可能为慢性炎症性疾病（如CAP）的铁调节失调提供治疗策略。

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Impact of p. Gingivalis-induced chronic apical periodontitis on systemic iron homeostasis via the hepatic IL-6/STAT3/Hepcidin signaling pathway

Background and Aims

Chronic apical periodontitis (CAP), an inflammatory disease of the oral cavity caused by bacterial infections with Porphyromonas gingivalis (P. gingivalis) as a key pathogen, has been associated with systemic effects, potentially influencing distant organs including liver. The liver plays a key role in iron metabolism and immunity by hepcidin. This study aims to investigate the impact of P. gingivalis-induced CAP on liver and systemic iron metabolism, focusing on the role of the IL-6/STAT3 signaling pathway in hepatic hepcidin synthesis.

Methods

A murine model of CAP was established by pulp chamber infection with P. gingivalis. Serum levels of IL-6, ferritin, and hepcidin were measured via ELISA. High-throughput sequencing was used to analyze hepatic gene expression, and immunohistochemistry with fluorescent staining was performed to validate protein expression in liver tissues.

Results

CAP led to significant changes in serum iron, ferritin, and IL-6. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed enrichment in pathways like JAK/STAT signaling and acute-phase responses, and gene set enrichment analysis (GSEA) also indicated activation of IL-6/JAK/STAT3 signaling pathway. Iimmunofluorescence confirmed increased IL-6, p-STAT3, and hepcidin expression. These levels were alleviated by stattic treatment, mitigating CAP-induced inflammatory and iron-regulatory effects.

Conclusion

P. gingivalis-induced CAP triggered systemic inflammation and disrupts iron metabolism via the IL-6/STAT3 signaling pathway, potentially affecting liver function. Targeting this pathway may offer therapeutic strategies for managing iron dysregulation in chronic inflammatory diseases like CAP.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

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.