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

IF 9.3 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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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.