CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation

Fu, Junfen; Lehmann, Christian; Wang, Xinning; Wahlbuhl, Mandy; Allabauer, Ida; Wilde, Benjamin; Amon, Lukas; Dolff, Sebastian; Cesnjevar, R.; Kribben, Andreas; Woelfle, Joachim; Rascher, Wolfgang; Hoyer, Peter F.; Dudziak, Diana; Witzke, Oliver; Hoerning, André

doi:10.1038/s41598-021-03115-z

Cited by 7 publications

(3 citation statements)

References 95 publications

(114 reference statements)

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“…ROC curves and overall survival analysis revealed a high diagnostic and prognostic power of the model on both the training cohorts (Supplementary Figure 8A) and the validation cohorts, which consisted of samples in GSE21374 excluding those in the training set (Figure 4D). Among these genes, CD44, CXCR4, PRDX2, and UBB were significantly related to transplantation rejection and poor survival (Figure 4E), which were also proved by researchers' studies (56)(57)(58)(59). The other four were newly discovered genes potentially playing key roles in rejection and graft failure (Figure 4E).…”

Section: Ptpn6 Is a Novel Signaling Molecular Inducing Stat4 Signalin...supporting

confidence: 58%

T Cells With Activated STAT4 Drive the High-Risk Rejection State to Renal Allograft Failure After Kidney Transplantation

et al. 2022

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In kidney transplantation, deteriorated progression of rejection is considered to be a leading course of postoperative mortality. However, the conventional histologic diagnosis is limited in reading the rejection status at the molecular level, thereby triggering mismatched pathogenesis with clinical phenotypes. Here, by applying uniform manifold approximation and projection and Leiden algorithms to 2,611 publicly available microarray datasets of renal transplantation, we uncovered six rejection states with corresponding signature genes and revealed a high-risk (HR) state that was essential in promoting allograft loss. By identifying cell populations from single-cell RNA sequencing data that were associated with the six rejection states, we identified a T-cell population to be the pathogenesis-triggering cells associated with the HR rejection state. Additionally, by constructing gene regulatory networks, we identified that activated STAT4, as a core transcription factor that was regulated by PTPN6 in T cells, was closely linked to poor allograft function and prognosis. Taken together, our study provides a novel strategy to help with the precise diagnosis of kidney allograft rejection progression, which is powerful in investigating the underlying molecular pathogenesis, and therefore, for further clinical intervention.

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Section: Ptpn6 Is a Novel Signaling Molecular Inducing Stat4 Signalin...supporting

confidence: 58%

T Cells With Activated STAT4 Drive the High-Risk Rejection State to Renal Allograft Failure After Kidney Transplantation

et al. 2022

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“…CXCR4 leads to enhanced proliferation, migration, and invasion of tumor cells by binding to CXCL12 and activating various downstream signaling pathways ( 28 ). Some studies on the role of CXCR4 in immune rejection show that its antagonist can effectively reduce the intensity of rejection after transplantation ( 29 , 30 ). These observations are consistent with our results.…”

Section: Resultsmentioning

confidence: 99%

Single-Cell Transcriptome Analysis of Chronic Antibody-Mediated Rejection After Renal Transplantation

Kong

Zhong

et al. 2022

Front. Immunol.

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Renal transplantation is currently the most effective treatment for end-stage renal disease. However, chronic antibody-mediated rejection (cABMR) remains a serious obstacle for the long-term survival of patients with renal transplantation and a problem to be solved. At present, the role and mechanism underlying immune factors such as T- and B- cell subsets in cABMR after renal transplantation remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood monocytes (PBMCs) from cABMR and control subjects was performed to define the transcriptomic landscape at single-cell resolution. A comprehensive scRNA-seq analysis was performed. The results indicated that most cell types in the cABMR patients exhibited an intense interferon response and release of proinflammatory cytokines. In addition, we found that the expression of MT-ND6, CXCL8, NFKBIA, NFKBIZ, and other genes were up-regulated in T- and B-cells and these genes were associated with pro-inflammatory response and immune regulation. Western blot and qRT-PCR experiments also confirmed the up-regulated expression of these genes in cABMR. GO and KEGG enrichment analyses indicated that the overexpressed genes in T- and B-cells were mainly enriched in inflammatory pathways, including the TNF, IL-17, and Toll-like receptor signaling pathways. Additionally, MAPK and NF-κB signaling pathways were also involved in the occurrence and development of cABMR. This is consistent with the experimental results of Western blot. Trajectory analysis assembled the T-cell subsets into three differentiation paths with distinctive phenotypic and functional prog rams. CD8 effector T cells and γδ T cells showed three different differentiation trajectories, while CD8_MAI T cells and naive T cells primarily had two differentiation trajectories. Cell-cell interaction analysis revealed strong T/B cells and neutrophils activation in cABMR. Thus, the study offers new insight into pathogenesis and may have implications for the identification of novel therapeutic targets for cABMR.

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“…TGFBI can promote renal fibrosis [ 71 ]. The antagonist of CXCR4 effectively reduces the rejection intensity after transplantation [ 72 , 73 ]. The positive correlation between hypoxia-related genes and PTPRC, CD8A, CD86, ITGAM, and CCR5 may be associated with allograft rejection after the kidney transplant.…”

Section: Discussionmentioning

confidence: 99%

Uncover diagnostic immunity/hypoxia/ferroptosis/epithelial mesenchymal transformation-related CCR5, CD86, CD8A, ITGAM, and PTPRC in kidney transplantation patients with allograft rejection

Wang

et al. 2022

Renal Failure

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The aim of this study was to identify predictive immunity/hypoxia/ferroptosis/epithelial mesenchymal transformation (EMT)-related biomarkers, pathways and new drugs in allograft rejection in kidney transplant patients. First, gene expression data were downloaded followed by identification of differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA) and protein–protein interaction (PPI) analysis. Second, diagnostic model was construction based on key genes, followed by correlation analysis between immune/hypoxia/ferroptosis/EMT and key diagnostic genes. Finally, drug prediction of diagnostic key genes was carried out. Five diagnostic genes were further identified, including CCR5, CD86, CD8A, ITGAM, and PTPRC, which were positively correlated with allograft rejection after the kidney transplant. Highly infiltrated immune cells, highly expression of hypoxia-related genes and activated status of EMT were significantly positively correlated with five diagnostic genes. Interestingly, suppressors of ferroptosis (SOFs) and drivers of ferroptosis (DOFs) showed a complex regulatory relationship between ferroptosis and five diagnostic genes. CD86, CCR5, and ITGAM were respectively drug target of ABATACEPT, MARAVIROC, and CLARITHROMYCIN. PTPRC was drug target of both PREDNISONE and EPOETIN BETA. In conclusion, the study could be useful in understanding changes in the microenvironment within transplantation, which may promote or sustain the development of allograft rejection after kidney transplantation.

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CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation

Cited by 7 publications

References 95 publications

T Cells With Activated STAT4 Drive the High-Risk Rejection State to Renal Allograft Failure After Kidney Transplantation

T Cells With Activated STAT4 Drive the High-Risk Rejection State to Renal Allograft Failure After Kidney Transplantation

Single-Cell Transcriptome Analysis of Chronic Antibody-Mediated Rejection After Renal Transplantation

Uncover diagnostic immunity/hypoxia/ferroptosis/epithelial mesenchymal transformation-related CCR5, CD86, CD8A, ITGAM, and PTPRC in kidney transplantation patients with allograft rejection

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