雷帕霉素揭示神经肽Y在关节炎衰老和炎症途径中的调节作用

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides Pub Date : 2025-06-16 DOI:10.1016/j.npep.2025.102533

Susana Aideé González-Chávez , Eduardo Chaparro-Barrera , Mario Loya-Rivera , Alejandra Jazmín Rodríguez-Castillo , Rodrigo Prieto-Carrasco , Renato J. Aguilera , Ana P. Betancourt , Jonathon E. Mohl , Daniel Alberto Ruizesparza-Hinojos , Sergio de Jesús Ramírez-Pérez , Mercedes Bermúdez , César Pacheco-Tena

{"title":"雷帕霉素揭示神经肽Y在关节炎衰老和炎症途径中的调节作用","authors":"Susana Aideé González-Chávez , Eduardo Chaparro-Barrera , Mario Loya-Rivera , Alejandra Jazmín Rodríguez-Castillo , Rodrigo Prieto-Carrasco , Renato J. Aguilera , Ana P. Betancourt , Jonathon E. Mohl , Daniel Alberto Ruizesparza-Hinojos , Sergio de Jesús Ramírez-Pérez , Mercedes Bermúdez , César Pacheco-Tena","doi":"10.1016/j.npep.2025.102533","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by immune dysregulation and joint destruction. Cellular senescence has been implicated in the progression of RA through the senescence-associated secretory phenotype (SASP), yet its molecular links to inflammation remain unclear. Rapamycin, an mTOR inhibitor with anti-inflammatory and anti-senescence properties, provides a valuable tool for exploring these mechanisms.</div></div><div><h3>Objective</h3><div>To investigate the link between senescence and inflammation in a murine model of RA by comparing the transcriptome of diseased joints in rapamycin-treated and untreated mice.</div></div><div><h3>Methods</h3><div>Collagen-induced arthritis was established in DBA/1 mice, followed by 40 days of rapamycin treatment. RNA sequencing and bioinformatic analyses were performed to identify differentially expressed genes and altered signaling pathways. RT-qPCR and immunohistochemistry validated candidate genes. Functional assays were conducted in fibroblast-like synoviocytes (FLS) following <em>Npy</em> silencing.</div></div><div><h3>Results</h3><div>Rapamycin treatment reduced the incidence and severity of arthritis while modulating senescence- and autophagy-related pathways. Transcriptomic analysis identified neuropeptide Y (<em>Npy</em>) as a differentially expressed gene linking senescence and inflammation, with reduced protein levels following rapamycin treatment, similar to TNF and β-galactosidase. NPY receptor expression (<em>Npy1r</em> and <em>Npy2r</em>) and autophagy-related genes (<em>Sirt1</em>, <em>Sirt6</em>, and <em>Lc3b</em>) were also modulated in vivo. In vitro, <em>Npy</em> silencing in FLS significantly reduced the expression of the SASP cytokines <em>Tnfa</em>, <em>Il1b</em>, and <em>Il6</em>, downregulated <em>Npy1r</em> and <em>Npy2r</em>, and increased <em>Sirt1</em> expression.</div></div><div><h3>Conclusion</h3><div>This study identifies <em>Npy</em> as a modulator of inflammation and senescence-related pathways in arthritis. Its regulation by rapamycin and impact on sirtuins, autophagy, and NPY receptor expression suggest a broader role in RA pathogenesis.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"112 ","pages":"Article 102533"},"PeriodicalIF":2.5000,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Rapamycin reveals neuropeptide Y as a regulator of senescence and inflammatory pathways in arthritis\",\"authors\":\"Susana Aideé González-Chávez , Eduardo Chaparro-Barrera , Mario Loya-Rivera , Alejandra Jazmín Rodríguez-Castillo , Rodrigo Prieto-Carrasco , Renato J. Aguilera , Ana P. Betancourt , Jonathon E. Mohl , Daniel Alberto Ruizesparza-Hinojos , Sergio de Jesús Ramírez-Pérez , Mercedes Bermúdez , César Pacheco-Tena\",\"doi\":\"10.1016/j.npep.2025.102533\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by immune dysregulation and joint destruction. Cellular senescence has been implicated in the progression of RA through the senescence-associated secretory phenotype (SASP), yet its molecular links to inflammation remain unclear. Rapamycin, an mTOR inhibitor with anti-inflammatory and anti-senescence properties, provides a valuable tool for exploring these mechanisms.</div></div><div><h3>Objective</h3><div>To investigate the link between senescence and inflammation in a murine model of RA by comparing the transcriptome of diseased joints in rapamycin-treated and untreated mice.</div></div><div><h3>Methods</h3><div>Collagen-induced arthritis was established in DBA/1 mice, followed by 40 days of rapamycin treatment. RNA sequencing and bioinformatic analyses were performed to identify differentially expressed genes and altered signaling pathways. RT-qPCR and immunohistochemistry validated candidate genes. Functional assays were conducted in fibroblast-like synoviocytes (FLS) following <em>Npy</em> silencing.</div></div><div><h3>Results</h3><div>Rapamycin treatment reduced the incidence and severity of arthritis while modulating senescence- and autophagy-related pathways. Transcriptomic analysis identified neuropeptide Y (<em>Npy</em>) as a differentially expressed gene linking senescence and inflammation, with reduced protein levels following rapamycin treatment, similar to TNF and β-galactosidase. NPY receptor expression (<em>Npy1r</em> and <em>Npy2r</em>) and autophagy-related genes (<em>Sirt1</em>, <em>Sirt6</em>, and <em>Lc3b</em>) were also modulated in vivo. In vitro, <em>Npy</em> silencing in FLS significantly reduced the expression of the SASP cytokines <em>Tnfa</em>, <em>Il1b</em>, and <em>Il6</em>, downregulated <em>Npy1r</em> and <em>Npy2r</em>, and increased <em>Sirt1</em> expression.</div></div><div><h3>Conclusion</h3><div>This study identifies <em>Npy</em> as a modulator of inflammation and senescence-related pathways in arthritis. Its regulation by rapamycin and impact on sirtuins, autophagy, and NPY receptor expression suggest a broader role in RA pathogenesis.</div></div>\",\"PeriodicalId\":19254,\"journal\":{\"name\":\"Neuropeptides\",\"volume\":\"112 \",\"pages\":\"Article 102533\"},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2025-06-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuropeptides\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0143417925000332\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuropeptides","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0143417925000332","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}

引用次数: 0

摘要

类风湿性关节炎（RA）是一种以免疫失调和关节破坏为特征的慢性炎症性疾病。细胞衰老通过衰老相关分泌表型（SASP）与RA的进展有关，但其与炎症的分子联系尚不清楚。雷帕霉素是一种具有抗炎和抗衰老特性的mTOR抑制剂，为探索这些机制提供了有价值的工具。目的通过比较雷帕霉素治疗和未治疗小鼠病变关节的转录组，探讨小鼠RA模型中衰老与炎症的关系。方法建立DBA/1小鼠胶原诱导关节炎模型，给予雷帕霉素治疗40 d。进行RNA测序和生物信息学分析以鉴定差异表达基因和改变的信号通路。RT-qPCR和免疫组织化学验证候选基因。Npy沉默后，对成纤维细胞样滑膜细胞（FLS）进行功能测定。结果雷帕霉素治疗降低了关节炎的发病率和严重程度，同时调节了衰老和自噬相关途径。转录组学分析发现神经肽Y （Npy）是与衰老和炎症相关的差异表达基因，在雷帕霉素治疗后蛋白水平降低，类似于TNF和β-半乳糖苷酶。NPY受体表达（Npy1r和Npy2r）和自噬相关基因（Sirt1， Sirt6和Lc3b）也在体内被调节。在体外，Npy沉默在FLS中显著降低SASP细胞因子Tnfa、Il1b和Il6的表达，下调Npy1r和Npy2r的表达，增加Sirt1的表达。结论本研究确定Npy是关节炎炎症和衰老相关途径的调节剂。雷帕霉素对其的调控以及对sirtuins、自噬和NPY受体表达的影响表明其在RA发病机制中具有更广泛的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Rapamycin reveals neuropeptide Y as a regulator of senescence and inflammatory pathways in arthritis

Background

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by immune dysregulation and joint destruction. Cellular senescence has been implicated in the progression of RA through the senescence-associated secretory phenotype (SASP), yet its molecular links to inflammation remain unclear. Rapamycin, an mTOR inhibitor with anti-inflammatory and anti-senescence properties, provides a valuable tool for exploring these mechanisms.

Objective

To investigate the link between senescence and inflammation in a murine model of RA by comparing the transcriptome of diseased joints in rapamycin-treated and untreated mice.

Methods

Collagen-induced arthritis was established in DBA/1 mice, followed by 40 days of rapamycin treatment. RNA sequencing and bioinformatic analyses were performed to identify differentially expressed genes and altered signaling pathways. RT-qPCR and immunohistochemistry validated candidate genes. Functional assays were conducted in fibroblast-like synoviocytes (FLS) following Npy silencing.

Results

Rapamycin treatment reduced the incidence and severity of arthritis while modulating senescence- and autophagy-related pathways. Transcriptomic analysis identified neuropeptide Y (Npy) as a differentially expressed gene linking senescence and inflammation, with reduced protein levels following rapamycin treatment, similar to TNF and β-galactosidase. NPY receptor expression (Npy1r and Npy2r) and autophagy-related genes (Sirt1, Sirt6, and Lc3b) were also modulated in vivo. In vitro, Npy silencing in FLS significantly reduced the expression of the SASP cytokines Tnfa, Il1b, and Il6, downregulated Npy1r and Npy2r, and increased Sirt1 expression.

Conclusion

This study identifies Npy as a modulator of inflammation and senescence-related pathways in arthritis. Its regulation by rapamycin and impact on sirtuins, autophagy, and NPY receptor expression suggest a broader role in RA pathogenesis.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Neuropeptides 医学-内分泌学与代谢

CiteScore

5.40

自引率

6.90%

发文量

审稿时长

>12 weeks

期刊介绍： The aim of Neuropeptides is the rapid publication of original research and review articles, dealing with the structure, distribution, actions and functions of peptides in the central and peripheral nervous systems. The explosion of research activity in this field has led to the identification of numerous naturally occurring endogenous peptides which act as neurotransmitters, neuromodulators, or trophic factors, to mediate nervous system functions. Increasing numbers of non-peptide ligands of neuropeptide receptors have been developed, which act as agonists or antagonists in peptidergic systems. The journal provides a unique opportunity of integrating the many disciplines involved in all neuropeptide research. The journal publishes articles on all aspects of the neuropeptide field, with particular emphasis on gene regulation of peptide expression, peptide receptor subtypes, transgenic and knockout mice with mutations in genes for neuropeptides and peptide receptors, neuroanatomy, physiology, behaviour, neurotrophic factors, preclinical drug evaluation, clinical studies, and clinical trials.