The Role of CXCR3 and Associated Chemokines in the Development of Atherosclerosis and During Myocardial Infarction

Szentes, Veronika; Gazdag, M.; Szokodi, István; Dézsi, Csaba András

doi:10.3389/fimmu.2018.01932

Cited by 53 publications

(39 citation statements)

References 66 publications

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“…In addition to CCL2, we identified other four hub genes closely related to postLVAD pathophysiology: CX3CR1 , CD163 , TLR7 , and SERPINE1 , which involve in chemokine binding, local inflammation induction, innate immunity activation, and fibrinolysis, respectively. All of these hub genes participate in cardiac inflammatory responses and have profound associations with chemokine signaling, which is well consistent with the result of KEGG pathway analysis. Evidently, the chemokine pathway plays a decisive role in the postLVAD pathophysiology.…”

Section: Discussionsupporting

confidence: 86%

Effects of left ventricular assist device on heart failure patients: A bioinformatics analysis

Chen

et al. 2020

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With the acceleration of demographic aging, heart failure has become a global public health issue. Left ventricular assist device (LVAD) provides a therapeutic option serving as a bridge to transplantation or destination treatment for end‐stage heart failure. However, neither the molecular mechanism nor the gene expression profile of LVAD pathophysiology is well understood. Microarray dataset (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE21610) was retrieved from the online database of the gene expression omnibus (GEO). Differentially expressed genes (DEGs) between microarrays obtained before and after LVAD therapy were analyzed using GEO2R. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis were carried out, followed by protein–protein interaction (PPI) network construction, which was further visualized by the Cytoscape software. Finally, a target gene‐microRNA (miRNA) network was built using the NetworkAnalyst to predict potential miRNA interactions. A total of 36 upregulated DEGs and 14 downregulated DEGs were screened out. Five hub genes with the highest degree of connectivity were identified, including CCL2, CX3CR1, CD163, TLR7, and SERPINE1. CCL2 was identified as the most outstanding hub gene which is specially regulated by miR‐124, miR‐141, and miR‐495. Our study indicates that CCL2 is crucial to the LVAD pathophysiology. The identified hub genes may be involved in cardiac inflammatory responses, remodeling, and the chemokine signaling pathway. These DEGs, pathways, hub genes, miRNAs are valuable for further investigations. This study provides a better understanding of the gene expression profile in LVAD pathophysiology.

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Section: Discussionsupporting

confidence: 86%

Effects of left ventricular assist device on heart failure patients: A bioinformatics analysis

Chen

et al. 2020

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“…HCMV latent infection of monocytes is also known to manipulate the recruitment of neutrophils ( 75 ) as well as the motility of latently infected monocytes to increase their trans endothelial migration ( 76 ). The association of persistent HCMV infection with vascular disease could also be partly explained by recruitment of activated T cells to peripheral sites of latency, as demonstrated here, as it is long established that CXCR3 expressing CD4+ T cells are recruited to atherosclerotic plaque sites ( 77 ). Therefore, the evidence from this study using an ex vivo model of latently infected monocytes, suggests potential avenues for future investigations looking for CMV reactivation in peripheral tissue sites in association with CXCL10 production and recruitment of CXCR3 expressing activated T cells.…”

Section: Discussionsupporting

confidence: 53%

Latent Cytomegalovirus-Driven Recruitment of Activated CD4+ T Cells Promotes Virus Reactivation

et al. 2021

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Human cytomegalovirus (HCMV) infection is not cleared by the initial immune response but persists for the lifetime of the host, in part due to its ability to establish a latent infection in cells of the myeloid lineage. HCMV has been shown to manipulate the secretion of cellular proteins during both lytic and latent infection; with changes caused by latent infection mainly investigated in CD34+ progenitor cells. Whilst CD34+ cells are generally bone marrow resident, their derivative CD14+ monocytes migrate to the periphery where they briefly circulate until extravasation into tissue sites. We have analyzed the effect of HCMV latent infection on the secretome of CD14+ monocytes, identifying an upregulation of both CCL8 and CXCL10 chemokines in the CD14+ latency-associated secretome. Unlike CD34+ cells, the CD14+ latency-associated secretome did not induce migration of resting immune cell subsets but did induce migration of activated NK and T cells expressing CXCR3 in a CXCL10 dependent manner. As reported in CD34+ latent infection, the CD14+ latency-associated secretome also suppressed the anti-viral activity of stimulated CD4+ T cells. Surprisingly, however, co-culture of activated autologous CD4+ T cells with latently infected monocytes resulted in reactivation of HCMV at levels comparable to those observed using M-CSF and IL-1β cytokines. We propose that these events represent a potential strategy to enable HCMV reactivation and local dissemination of the virus at peripheral tissue sites.

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“…Apabetalone treatment also potently downregulated the transcription of genes differentially induced by IFNγ in DM2 + CVD monocytes, including the pro-inflammatory cytokine TNF gene (33% reduction), and monocyte chemokine genes CCL7 and CCL8 (90% and 85% reduction, respectively). Additional chemokines that promote chemotaxis and tissue extravasation, CCL2 [62,64], CXCL9 [79] and CXCL10 [79], were induced by IFNγ in both monocyte populations and were strongly suppressed by apabetalone (91%, 80% and 61% reduction, respectively) ( Table 3). BETi treatment is thus predicted to reduce the migratory phenotype of DM2 + CVD monocytes, potentially preventing atherosclerotic plaque infiltration by activated monocytes.…”

Section: Discussionmentioning

confidence: 99%

BET protein inhibitor apabetalone (RVX-208) suppresses pro-inflammatory hyper-activation of monocytes from patients with cardiovascular disease and type 2 diabetes

et al. 2020

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Background Patients with cardiovascular disease (CVD) and type 2 diabetes (DM2) have a high residual risk for experiencing a major adverse cardiac event. Dysregulation of epigenetic mechanisms of gene transcription in innate immune cells contributes to CVD development but is currently not targeted by therapies. Apabetalone (RVX-208) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins—histone acetylation readers that drive pro-inflammatory and pro-atherosclerotic gene transcription. Here, we assess the impact of apabetalone on ex vivo inflammatory responses of monocytes from DM2 + CVD patients. Results Monocytes isolated from DM2 + CVD patients and matched controls were treated ex vivo with apabetalone, interferon γ (IFNγ), IFNγ + apabetalone or vehicle and phenotyped for gene expression and protein secretion. Unstimulated DM2 + CVD monocytes had higher baseline IL-1α, IL-1β and IL-8 cytokine gene expression and Toll-like receptor (TLR) 2 surface abundance than control monocytes, indicating pro-inflammatory activation. Further, DM2 + CVD monocytes were hyper-responsive to stimulation with IFNγ, upregulating genes within cytokine and NF-κB pathways > 30% more than control monocytes (p < 0.05). Ex vivo apabetalone treatment countered cytokine secretion by DM2 + CVD monocytes at baseline (GROα and IL-8) and during IFNγ stimulation (IL-1β and TNFα). Apabetalone abolished pro-inflammatory hyper-activation by reducing TLR and cytokine gene signatures more robustly in DM2 + CVD versus control monocytes. Conclusions Monocytes isolated from DM2 + CVD patients receiving standard of care therapies are in a hyper-inflammatory state and hyperactive upon IFNγ stimulation. Apabetalone treatment diminishes this pro-inflammatory phenotype, providing mechanistic insight into how BET protein inhibition may reduce CVD risk in DM2 patients.

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The Role of CXCR3 and Associated Chemokines in the Development of Atherosclerosis and During Myocardial Infarction

Cited by 53 publications

References 66 publications

Effects of left ventricular assist device on heart failure patients: A bioinformatics analysis

Effects of left ventricular assist device on heart failure patients: A bioinformatics analysis

Latent Cytomegalovirus-Driven Recruitment of Activated CD4+ T Cells Promotes Virus Reactivation

BET protein inhibitor apabetalone (RVX-208) suppresses pro-inflammatory hyper-activation of monocytes from patients with cardiovascular disease and type 2 diabetes

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