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Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression

Glioma is the most common of all central nervous system (CNS) malignancies and is associated with a poor prognosis. Pyroptosis has been proven to be associated with the progression of multiple tumors and CNS diseases. However, the relationships between pyroptosis and clinical prognosis and immune ce...

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Autores principales: Li, Lin, Wu, Leyang, Yin, Xingpeng, Li, Chenyang, Hua, Zichun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9529448/
https://www.ncbi.nlm.nih.gov/pubmed/36199426
http://dx.doi.org/10.1155/2022/1803544
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author Li, Lin
Wu, Leyang
Yin, Xingpeng
Li, Chenyang
Hua, Zichun
author_facet Li, Lin
Wu, Leyang
Yin, Xingpeng
Li, Chenyang
Hua, Zichun
author_sort Li, Lin
collection PubMed
description Glioma is the most common of all central nervous system (CNS) malignancies and is associated with a poor prognosis. Pyroptosis has been proven to be associated with the progression of multiple tumors and CNS diseases. However, the relationships between pyroptosis and clinical prognosis and immune cell infiltration are unclear in glioma. In this study, we conducted a comprehensive exploration of pyroptosis in glioma. First, prognosis-related genes were screened at each key regulatory locus in the pyroptosis pathway, and the prognostic ability and coexpression relationships of GSDMD and its upstream pathway genes NLRC4/CASP1/CASP4 were identified and well validated in multiple datasets. Tissue microarray-based immunohistochemistry results showed higher levels of NLRC4 and N-terminal GSDMD in high-grade gliomas, providing conclusive evidence of pyroptosis in gliomas. The robustness of the prognostic model based on these four genes was well validated in TCGA and CGGA cohorts. Bulk RNA-seq-based analysis showed that the group defined as the high-risk group according to the model showed activation of multiple inflammatory response pathways and impaired synaptic gene expression and had a higher infiltration of bone marrow-derived macrophages (BMDMs) and a hypersuppressed immune microenvironment. More importantly, three independent single-cell RNA-seq (scRNA-seq) datasets demonstrated that tumor-infiltrating macrophages, particularly BMDMs but not tissue-resident microglia, showed significant coexpression of the GSDMD and CASP genes, and BMDMs from high-grade gliomas accounted for a higher proportion of immune infiltrating cells and had higher expression of pyroptosis genes. Finally, we revealed the activation of pathways in response to LPS/bacteria and oxidative stress during BMDM development toward the pyroptosis cell fate by pseudotime trajectory analysis, suggesting potential BMDM pyroptosis initiators. The above results provide not only novel insights into the pathological mechanisms of glioma but also novel therapeutic targets for glioma, suggesting the potential application of pyroptosis inhibitors (e.g., disulfiram).
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spelling pubmed-95294482022-10-04 Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression Li, Lin Wu, Leyang Yin, Xingpeng Li, Chenyang Hua, Zichun Oxid Med Cell Longev Research Article Glioma is the most common of all central nervous system (CNS) malignancies and is associated with a poor prognosis. Pyroptosis has been proven to be associated with the progression of multiple tumors and CNS diseases. However, the relationships between pyroptosis and clinical prognosis and immune cell infiltration are unclear in glioma. In this study, we conducted a comprehensive exploration of pyroptosis in glioma. First, prognosis-related genes were screened at each key regulatory locus in the pyroptosis pathway, and the prognostic ability and coexpression relationships of GSDMD and its upstream pathway genes NLRC4/CASP1/CASP4 were identified and well validated in multiple datasets. Tissue microarray-based immunohistochemistry results showed higher levels of NLRC4 and N-terminal GSDMD in high-grade gliomas, providing conclusive evidence of pyroptosis in gliomas. The robustness of the prognostic model based on these four genes was well validated in TCGA and CGGA cohorts. Bulk RNA-seq-based analysis showed that the group defined as the high-risk group according to the model showed activation of multiple inflammatory response pathways and impaired synaptic gene expression and had a higher infiltration of bone marrow-derived macrophages (BMDMs) and a hypersuppressed immune microenvironment. More importantly, three independent single-cell RNA-seq (scRNA-seq) datasets demonstrated that tumor-infiltrating macrophages, particularly BMDMs but not tissue-resident microglia, showed significant coexpression of the GSDMD and CASP genes, and BMDMs from high-grade gliomas accounted for a higher proportion of immune infiltrating cells and had higher expression of pyroptosis genes. Finally, we revealed the activation of pathways in response to LPS/bacteria and oxidative stress during BMDM development toward the pyroptosis cell fate by pseudotime trajectory analysis, suggesting potential BMDM pyroptosis initiators. The above results provide not only novel insights into the pathological mechanisms of glioma but also novel therapeutic targets for glioma, suggesting the potential application of pyroptosis inhibitors (e.g., disulfiram). Hindawi 2022-09-26 /pmc/articles/PMC9529448/ /pubmed/36199426 http://dx.doi.org/10.1155/2022/1803544 Text en Copyright © 2022 Lin Li et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Li, Lin
Wu, Leyang
Yin, Xingpeng
Li, Chenyang
Hua, Zichun
Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression
title Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression
title_full Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression
title_fullStr Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression
title_full_unstemmed Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression
title_short Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression
title_sort bulk and single-cell transcriptome analyses revealed that the pyroptosis of glioma-associated macrophages participates in tumor progression and immunosuppression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9529448/
https://www.ncbi.nlm.nih.gov/pubmed/36199426
http://dx.doi.org/10.1155/2022/1803544
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