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SLAMF8 Participates in Acute Renal Transplant Rejection via TLR4 Pathway on Pro-Inflammatory Macrophages
BACKGROUND: Acute rejection (AR) in kidney transplantation is an established risk factor that reduces the survival rate of allografts. Despite standard immunosuppression, molecules with regulatory control in the immune pathway of AR can be used as important targets for therapeutic operations to prev...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012444/ https://www.ncbi.nlm.nih.gov/pubmed/35432371 http://dx.doi.org/10.3389/fimmu.2022.846695 |
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author | Teng, Lisha Shen, Lingling Zhao, Wenjun Wang, Cuili Feng, Shi Wang, Yucheng Bi, Yan Rong, Song Shushakova, Nelli Haller, Hermann Chen, Jianghua Jiang, Hong |
author_facet | Teng, Lisha Shen, Lingling Zhao, Wenjun Wang, Cuili Feng, Shi Wang, Yucheng Bi, Yan Rong, Song Shushakova, Nelli Haller, Hermann Chen, Jianghua Jiang, Hong |
author_sort | Teng, Lisha |
collection | PubMed |
description | BACKGROUND: Acute rejection (AR) in kidney transplantation is an established risk factor that reduces the survival rate of allografts. Despite standard immunosuppression, molecules with regulatory control in the immune pathway of AR can be used as important targets for therapeutic operations to prevent rejection. METHODS: We downloaded the microarray data of 15 AR patients and 37 non-acute rejection (NAR) patients from Gene Expression Omnibus (GEO). Gene network was constructed, and genes were classified into different modules using weighted gene co-expression network analysis (WGCNA). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cytoscape were applied for the hub genes in the most related module to AR. Different cell types were explored by xCell online database and single-cell RNA sequencing. We also validated the SLAMF8 and TLR4 levels in Raw264.7 and human kidney tissues of TCMR. RESULTS: A total of 1,561 differentially expressed genes were filtered. WGCNA was constructed, and genes were classified into 12 modules. Among them, the green module was most closely associated with AR. These genes were significantly enriched in 20 pathway terms, such as cytokine–cytokine receptor interaction, chemokine signaling pathway, and other important regulatory processes. Intersection with GS > 0.4, MM > 0.9, the top 10 MCC values and DEGs in the green module, and six hub genes (DOCK2, NCKAP1L, IL2RG, SLAMF8, CD180, and PTPRE) were identified. Their expression levels were all confirmed to be significantly elevated in AR patients in GEO, Nephroseq, and quantitative real-time PCR (qRT-PCR). Single-cell RNA sequencing showed that AR patient had a higher percentage of native T, CD1C+_B DC, NKT, NK, and monocytes in peripheral blood mononuclear cells (PBMCs). Xcell enrichment scores of 20 cell types were significantly different (p<0.01), mostly immune cells, such as B cells, CD4+ Tem, CD8+ T cells, CD8+ Tcm, macrophages, M1, and monocytes. GSEA suggests that highly expressed six hub genes are correlated with allograft rejection, interferon γ response, interferon α response, and inflammatory response. In addition, SLAMF8 is highly expressed in human kidney tissues of TCMR and in M1 phenotype macrophages of Raw264.7 cell line WGCNA accompanied by high expression of TLR4. CONCLUSION: This study demonstrates six hub genes and functionally enriched pathways related to AR. SLAMF8 is involved in the M1 macrophages via TLR4, which contributed to AR process. |
format | Online Article Text |
id | pubmed-9012444 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90124442022-04-16 SLAMF8 Participates in Acute Renal Transplant Rejection via TLR4 Pathway on Pro-Inflammatory Macrophages Teng, Lisha Shen, Lingling Zhao, Wenjun Wang, Cuili Feng, Shi Wang, Yucheng Bi, Yan Rong, Song Shushakova, Nelli Haller, Hermann Chen, Jianghua Jiang, Hong Front Immunol Immunology BACKGROUND: Acute rejection (AR) in kidney transplantation is an established risk factor that reduces the survival rate of allografts. Despite standard immunosuppression, molecules with regulatory control in the immune pathway of AR can be used as important targets for therapeutic operations to prevent rejection. METHODS: We downloaded the microarray data of 15 AR patients and 37 non-acute rejection (NAR) patients from Gene Expression Omnibus (GEO). Gene network was constructed, and genes were classified into different modules using weighted gene co-expression network analysis (WGCNA). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cytoscape were applied for the hub genes in the most related module to AR. Different cell types were explored by xCell online database and single-cell RNA sequencing. We also validated the SLAMF8 and TLR4 levels in Raw264.7 and human kidney tissues of TCMR. RESULTS: A total of 1,561 differentially expressed genes were filtered. WGCNA was constructed, and genes were classified into 12 modules. Among them, the green module was most closely associated with AR. These genes were significantly enriched in 20 pathway terms, such as cytokine–cytokine receptor interaction, chemokine signaling pathway, and other important regulatory processes. Intersection with GS > 0.4, MM > 0.9, the top 10 MCC values and DEGs in the green module, and six hub genes (DOCK2, NCKAP1L, IL2RG, SLAMF8, CD180, and PTPRE) were identified. Their expression levels were all confirmed to be significantly elevated in AR patients in GEO, Nephroseq, and quantitative real-time PCR (qRT-PCR). Single-cell RNA sequencing showed that AR patient had a higher percentage of native T, CD1C+_B DC, NKT, NK, and monocytes in peripheral blood mononuclear cells (PBMCs). Xcell enrichment scores of 20 cell types were significantly different (p<0.01), mostly immune cells, such as B cells, CD4+ Tem, CD8+ T cells, CD8+ Tcm, macrophages, M1, and monocytes. GSEA suggests that highly expressed six hub genes are correlated with allograft rejection, interferon γ response, interferon α response, and inflammatory response. In addition, SLAMF8 is highly expressed in human kidney tissues of TCMR and in M1 phenotype macrophages of Raw264.7 cell line WGCNA accompanied by high expression of TLR4. CONCLUSION: This study demonstrates six hub genes and functionally enriched pathways related to AR. SLAMF8 is involved in the M1 macrophages via TLR4, which contributed to AR process. Frontiers Media S.A. 2022-04-01 /pmc/articles/PMC9012444/ /pubmed/35432371 http://dx.doi.org/10.3389/fimmu.2022.846695 Text en Copyright © 2022 Teng, Shen, Zhao, Wang, Feng, Wang, Bi, Rong, Shushakova, Haller, Chen and Jiang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Teng, Lisha Shen, Lingling Zhao, Wenjun Wang, Cuili Feng, Shi Wang, Yucheng Bi, Yan Rong, Song Shushakova, Nelli Haller, Hermann Chen, Jianghua Jiang, Hong SLAMF8 Participates in Acute Renal Transplant Rejection via TLR4 Pathway on Pro-Inflammatory Macrophages |
title | SLAMF8 Participates in Acute Renal Transplant Rejection via TLR4 Pathway on Pro-Inflammatory Macrophages |
title_full | SLAMF8 Participates in Acute Renal Transplant Rejection via TLR4 Pathway on Pro-Inflammatory Macrophages |
title_fullStr | SLAMF8 Participates in Acute Renal Transplant Rejection via TLR4 Pathway on Pro-Inflammatory Macrophages |
title_full_unstemmed | SLAMF8 Participates in Acute Renal Transplant Rejection via TLR4 Pathway on Pro-Inflammatory Macrophages |
title_short | SLAMF8 Participates in Acute Renal Transplant Rejection via TLR4 Pathway on Pro-Inflammatory Macrophages |
title_sort | slamf8 participates in acute renal transplant rejection via tlr4 pathway on pro-inflammatory macrophages |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012444/ https://www.ncbi.nlm.nih.gov/pubmed/35432371 http://dx.doi.org/10.3389/fimmu.2022.846695 |
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