Department of Neurosurgery, Bundang CHA Medical Center, CHA University College of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, Republic of Korea.
Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Republic of Korea.
Inflamm Res. 2023 Apr;72(4):813-827. doi: 10.1007/s00011-023-01710-6. Epub 2023 Mar 10.
The present study was designed to explore the pathological role of non-canonical NLRC4 inflammasome in glioma.
This retrospective study included bioinformatical analysis, including survival, gene ontology, ssGSEA, cox regression, IPA and drug repositioning with TCGA and DepMap database. Experimental validations were conducted in glioma patient's sample and evaluated with histological or cellular functional analysis.
Clinical dataset analysis revealed that non-canonical NLRC4 inflammasomes significantly contribute to glioma progression and poor survival rates. Experimental validation was revealed that the expression of non-canonical NLRC4 inflammasomes were co-localized with astrocytes in malignant gliomas, with a sustained clinical correlation observed between astrocytes and inflammasome signatures. Indeed, the formation of an inflammatory microenvironment increased in malignant gliomas, leading to pyroptosis, known as inflammatory cell death. Molecular interaction analysis revealed that NF-κB pathways potentially serve as the connecting point between the canonical and noncanonical pathways of the NLRC4 inflammasome. Finally, drug repositioning analysis of non-canonical NLRC4 inflammasome-associated molecules revealed that MK-5108, PF4981517, and CTEP may represent effective options for glioma therapy.
The findings of this study suggest that non-canonical NLRC4 inflammasomes contribute to poor prognosis in patients with glioma and induce an inflammatory microenvironment. We propose the pathological phenomenon of non-canonical NLRC4 inflammasomes and several therapeutic strategies based on the modulation of the inflammatory tumor microenvironment.
本研究旨在探索非经典 NLRC4 炎性小体在神经胶质瘤中的病理作用。
本回顾性研究包括生物信息学分析，包括生存分析、基因本体论分析、ssGSEA 分析、cox 回归分析、IPA 分析和 TCGA 和 DepMap 数据库的药物重定位分析。在神经胶质瘤患者样本中进行了实验验证，并通过组织学或细胞功能分析进行了评估。
临床数据集分析表明，非经典 NLRC4 炎性小体显著促进神经胶质瘤的进展和降低生存率。实验验证表明，非经典 NLRC4 炎性小体的表达与恶性神经胶质瘤中的星形胶质细胞共定位，并且在星形胶质细胞和炎性小体特征之间观察到持续的临床相关性。事实上，恶性神经胶质瘤中炎症微环境的形成增加，导致细胞焦亡，即炎症性细胞死亡。分子相互作用分析表明，NF-κB 途径可能是 NLRC4 炎性小体的经典和非经典途径之间的连接点。最后，对非经典 NLRC4 炎性小体相关分子的药物重定位分析表明，MK-5108、PF4981517 和 CTEP 可能是神经胶质瘤治疗的有效选择。
本研究的结果表明，非经典 NLRC4 炎性小体导致神经胶质瘤患者预后不良，并诱导炎症微环境。我们提出了非经典 NLRC4 炎性小体的病理现象和几种基于炎症肿瘤微环境调节的治疗策略。
