CCL5/CCR5 axis in human diseases and related treatments

Zeng, Zhen; Lan, Tu; Wei, Yuquan; Wei, Xiawei

doi:10.1016/j.gendis.2021.08.004

Cited by 103 publications

(70 citation statements)

References 192 publications

(208 reference statements)

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“…CCL5 can mediate the migration of immune cells and promote lymphocyte migration in breast cancer cells [31]. Many autoimmune diseases are associated with increased levels of CCL5 and inversely associated with breast cancer risk [32, 33]. All this evidence supports the role of plasma CCL5 in breast tumor carcinogenesis.…”

Section: Discussionmentioning

confidence: 91%

The association between plasma chemokines and breast cancer risk and prognosis: A Mendelian randomization study

Zhang

Lin

et al. 2022

Preprint

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Background: Despite the potential role of several chemokines in the migration of cytotoxic immune cells to prohibit breast cancer cell proliferation, a comprehensive view of chemokines and the risk and prognosis of breast cancer is scarce, and little is known about their causal associations. Methods: With a two-sample Mendelian randomization (MR) approach, genetic instruments associated with 30 plasma chemokines were created. Their genetic associations with breast cancer risk and survival were extracted from the recent genome-wide association study, with available survival information for 96,661 patients. We further tested the associations between the polygenetic risk score (PRS) for chemokines and breast cancer in the UK Biobank cohort using logistic regression models. The association between chemokine expression in tumors and breast cancer survival was analyzed in the TCGA cohort with Cox regression models. Results: Plasma CCL5 was causally associated with the risk of breast cancer in the MR analysis, which was significant in the luminal and HER-2 enriched subtypes and further confirmed using PRS analysis (OR=0.94, 95% CI=0.89-1.00). A potential causal association with breast cancer survival was only found for plasma CCL19, especially for ER-positive patients. In addition, we also found an inverse association between CCL19 expression in tumors and breast cancer overall and relapse-free survival (HR=0.58, 95% CI=0.35-0.95). Conclusion: We observed an inverse association between genetic predisposition to CCL5 and the risk of breast cancer, while CCL19 was associated with breast cancer survival. These associations suggested the potential of these chemokines as tools for breast cancer prevention and treatment.

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Section: Discussionmentioning

confidence: 91%

The association between plasma chemokines and breast cancer risk and prognosis: A Mendelian randomization study

Zhang

Lin

et al. 2022

Preprint

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“…CCL5 is a potent chemoattractant for blood monocytes, memory T-helper cells, and eosinophils, which is important in recruiting T-cells into inflammatory sites, and also activates the apoptotic cell death pathway in T cells ( 46 ). Among these inverse correlations, CCL5 was negatively co-expressed with TLR1 (Pearson’s r = -0.675, p = 0.046), TLR2, TLR4 (Pearson’s r = -0.878, p = 0.002), TLR6 (Pearson’s r = -0.903, p = 0.001), and TLR8 (Pearson’s r = -0.818, p = 0.007), and T-bet was negatively co-expressed with TLR4 (Pearson’s r = -0.713, p = 0.031), TLR6 (Pearson’s r = -0.755, p = 0.019), and TLR8 (Pearson’s r = -0.837, p = 0.005).…”

Section: Resultsmentioning

confidence: 99%

“…To more clearly demonstrate this feature, Supplementary Figures 1C-F only showed the high correlations (defined as |r| > 0.73, p < 0.01). CCL5 is a potent chemoattractant for blood monocytes, memory T-helper cells, and eosinophils, which is important in recruiting T-cells into inflammatory sites, and also activates the apoptotic cell death pathway in T cells (46). Among these inverse correlations, CCL5 was negatively co-expressed with TLR1 (Pearson's r= -0.675, p= 0.046), TLR2, TLR4 (Pearson's r= -0.878, p= 0.002), TLR6 (Pearson's r= -0.903, p= 0.001), and TLR8 (Pearson's r= -0.818, p= 0.007), and T-bet was negatively co-expressed with TLR4 (Pearson's r= -0.713, p= 0.031), TLR6 (Pearson's r= -0.755, p= 0.019), and TLR8 (Pearson's r= -0.837, FIGURE 4 | Toll-like receptors (TLRs) and their correlation cluster distinguish active patients from inactive patients in TAK.…”

Section: Tlrs and Their Correlation Cluster Distinguish Active Patien...mentioning

confidence: 99%

Identification of the Association Between Toll-Like Receptors and T-Cell Activation in Takayasu’s Arteritis

Tian

Huang

et al. 2022

Front. Immunol.

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To explore the relationships between Toll-like receptors (TLRs) and the activation and differentiation of T-cells in Takayasu’s arteritis (TAK), using real-time fluorescence quantitative polymerase chain reaction, mRNA abundance of 29 target genes in peripheral blood mononuclear cells (PBMCs) were detected from 27 TAK patients and 10 healthy controls. Compared with the healthy control group, the untreated TAK group and the treated TAK group had an increased mRNA level of TLR2 and TLR4. A sample-to-sample matrix revealed that 80% of healthy controls could be separated from the TAK patients. Correlation analysis showed that the inactive-treated TAK group exhibited a unique pattern of inverse correlations between the TLRs gene clusters (including TLR1/2/4/6/8, BCL6, TIGIT, NR4A1, etc) and the gene cluster associated with T-cell activation and differentiation (including TCR, CD28, T-bet, GATA3, FOXP3, CCL5, etc). The dynamic gene co-expression network indicated the TAK groups had more active communication between TLRs and T-cell activation than healthy controls. BCL6, CCL5, FOXP3, GATA3, CD28, T-bet, TIGIT, IκBα, and NR4A1 were likely to have a close functional relation with TLRs at the inactive stage. The co-expression of TLR4 and TLR6 could serve as a biomarker of disease activity in treated TAK (the area under curve/sensitivity/specificity, 0.919/100%/90.9%). The largest gene co-expression cluster of the inactive-treated TAK group was associated with TLR signaling pathways, while the largest gene co-expression cluster of the active-treated TAK group was associated with the activation and differentiation of T-cells. The miRNA sequencing of the plasma exosomes combining miRDB, DIANA-TarBase, and miRTarBase databases suggested that the miR-548 family miR-584, miR-3613, and miR-335 might play an important role in the cross-talk between TLRs and T-cells at the inactive stage. This study found a novel relation between TLRs and T-cell in the pathogenesis of autoimmune diseases, proposed a new concept of TLR-co-expression signature which might distinguish different disease activity of TAK, and highlighted the miRNA of exosomes in TLR signaling pathway in TAK.

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“…We also constructed a protein-protein interaction network among differentially methylated and expressed genes (|log 2 FC| > 0.5, |diffMethy| > 0.1, and P < 0.05), in which CCL5 and CXCL10 were identified as the core genes of the network. CCL5 (chemokine ligand 5) and CXCL10 (CXC motif chemokine ligand 10) are chemokines responsible for facilitating inflammatory responses, including the adhesion and migration of different T cell subsets in immune responses, and are involved in various pathological processes including inflammation, chronic diseases, and cancers as well as the infection of COVID-19 (41,42). Interestingly, as key genes in the cytokine-cytokine receptor interaction signaling pathway, CCL5 and CXCL10 were also identified as core genes in our previous study in porcine aortic vascular endothelial cells infected with G. parasuis (19), and this prompted us to infer that these two chemokines may play a very important role in the immune response during G. parasuis infection and further study is necessary to confirm this.…”

Section: Discussionmentioning

confidence: 99%

Methylome and Transcriptome-Based Integration Analysis Identified Molecular Signatures Associated With Meningitis Induced by Glaesserella parasuis

Li-wei

Chen

et al. 2022

Front. Immunol.

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Glaesserella parasuis (G. parasuis) can elicit serious inflammatory responses and cause meningitis in piglets. Previous epigenetic studies have indicated that alterations in host DNA methylation may modify the inflammatory response to bacterial infection. However, to date, genome-wide analysis of the DNA methylome during meningitis caused by G. parasuis infection is still lacking. In this study, we employed an unbiased approach using deep sequencing to profile the DNA methylome and transcriptome from G. parasuis infected porcine brain (cerebrum) and integrated the data to identify key differential methylation regions/sites involved in the regulation of the inflammatory response. Results showed that DNA methylation patterns and gene expression profiles from porcine brain were changed after G. parasuis infection. The majority of the altered DNA methylation regions were found in the intergenic regions and introns and not associated with CpG islands, with only a low percentage occurring at promoter or exon regions. Integrated analysis of the DNA methylome and transcriptome identified a number of inversely and positively correlated genes between DNA methylation and gene expression, following the criteria of |log2FC| > 0.5, |diffMethy| > 0.1, and P < 0.05. Differential expression and methylation of two significant genes, semaphoring 4D (SEMA4D) and von Willebrand factor A domain containing 1 (VWA1), were validated by qRT-PCR and bisulfite sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses demonstrated that DNA methylation inversely correlated genes in G. parasuis infected porcine brains were mainly involved with cell adhesion molecules (CAMs), bacterial invasion of epithelial cells, RIG-1-like receptor signaling pathways, and hematopoietic cell lineage signaling pathways. In addition, a protein-protein interaction network of differentially methylated genes found potential candidate molecular interactions relevant to the pathology of G. parasuis infection. To the best of our knowledge, this is the first attempt to integrate the DNA methylome and transcriptome data from G. parasuis infected porcine brains. Our findings will help understanding the contribution of genome-wide DNA methylation to the pathogenesis of meningitis in pigs and developing epigenetic biomarkers and therapeutic targets for the treatment of G. parasuis induced meningitis.

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CCL5/CCR5 axis in human diseases and related treatments

Cited by 103 publications

References 192 publications

The association between plasma chemokines and breast cancer risk and prognosis: A Mendelian randomization study

The association between plasma chemokines and breast cancer risk and prognosis: A Mendelian randomization study

Identification of the Association Between Toll-Like Receptors and T-Cell Activation in Takayasu’s Arteritis

Methylome and Transcriptome-Based Integration Analysis Identified Molecular Signatures Associated With Meningitis Induced by Glaesserella parasuis

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