Therapeutic potential of targeting the IRF2/POSTN/Notch1 axis in nucleus pulposus cells for intervertebral disc degeneration.

IF 10.1 1区医学 Q1 IMMUNOLOGY Journal of Neuroinflammation Pub Date : 2025-01-22 DOI:10.1186/s12974-025-03335-4

Daxue Zhu, Zhaoheng Wang, Shijie Chen, Yanhu Li, Xuewen Kang

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Abstract

Background: Intervertebral disc degeneration (IDD) is a leading cause of low back pain, often linked to inflammation and pyroptosis in nucleus pulposus (NP) cells. The role of Periostin (POSTN) in IDD remains unclear.

Objective: This study aims to investigate the influence of POSTN on pyroptosis and NLRP3 inflammasome activation in NP cells during IDD.

Methods: IVD samples were collected from patients undergoing spinal surgery and classified according to the Pfirrmann grading system. Human NP cells were cultured and treated with IL-1β to induce a pyroptotic phenotype. Western blotting, Immunofluorescence (IF), and immunohistochemistry (IHC) assessed the expression levels of relevant proteins. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified the binding of IRF2 to the POSTN and GSDMD promoters and evaluated the activation levels of target genes. The severity of IDD was evaluated using MRI and histological analysis.

Results: Deletion of POSTN significantly alleviated IDD by suppressing NLRP3 inflammasome activity and pyroptosis in NP cells. POSTN was found to aggravate NP cell pyroptosis by activating the NLRP3 inflammasome through the NF-κB (P65) and cGAS/STING signaling pathways. Furthermore, POSTN interacted with Notch1 to induce NLRP3 expression. IRF2 was identified as a regulator of POSTN at the transcriptional level, contributing to NLRP3 activation and NP cell pyroptosis. IRF2 also directly induced the transcriptional expression of GSDMD, mediating pyroptosis in NP cells. Chemical screening identified Glucosyringic acid (GA) as a direct inhibitor of POSTN, which delayed IDD progression.

Conclusion: The study elucidates the pivotal role of POSTN in mediating NP cell pyroptosis through the NLRP3 inflammasome and highlights GA as a promising therapeutic candidate for IDD. These findings provide new insights into the molecular mechanisms of IDD and potential avenues for treatment.

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靶向髓核细胞IRF2/POSTN/Notch1轴治疗椎间盘退变的潜力。

背景：椎间盘退变（IDD）是腰痛的主要原因，通常与髓核（NP）细胞的炎症和焦下垂有关。Periostin （POSTN）在IDD中的作用尚不清楚。目的：本研究旨在探讨POSTN对IDD时NP细胞焦亡及NLRP3炎性体活化的影响。方法：收集脊柱手术患者IVD标本，按Pfirrmann分级系统进行分类。培养人NP细胞，用IL-1β处理后，细胞呈焦亡表型。Western blotting、Immunofluorescence （IF）和immunohistochemistry （IHC）检测相关蛋白的表达水平。染色质免疫沉淀（ChIP）和荧光素酶报告基因检测证实了IRF2与POSTN和GSDMD启动子的结合，并评估了靶基因的激活水平。通过MRI和组织学分析评估IDD的严重程度。结果：缺失POSTN可通过抑制NP细胞NLRP3炎性体活性和焦亡显著减轻IDD。POSTN通过NF-κB （P65）和cGAS/STING信号通路激活NLRP3炎性体，从而加重NP细胞的焦亡。此外，POSTN与Notch1相互作用诱导NLRP3表达。IRF2在转录水平上被认为是POSTN的调节因子，有助于NLRP3的激活和NP细胞的焦亡。IRF2还直接诱导GSDMD的转录表达，介导NP细胞的焦亡。化学筛选发现葡萄糖丁香酸（GA）是POSTN的直接抑制剂，可以延缓IDD的进展。结论：该研究阐明了POSTN通过NLRP3炎性体介导NP细胞焦亡的关键作用，并强调GA是治疗IDD的有希望的候选药物。这些发现为IDD的分子机制和潜在的治疗途径提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Neuroinflammation 医学-神经科学

CiteScore

15.90

自引率

3.20%

发文量

276

审稿时长

1 months

期刊介绍： The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.