Hemopoietic cell expression of the chemokine decoy receptor D6 is dynamic and regulated by GATA1

McKimmie, Clive S.; Fraser, Alasdair R.; Hansell, Chris; Gutiérrez, Laura; Philipsen, Sjaak; Connell, Laura; Rot, Antal; Kurowska‐Stolarska, Mariola; Carreño, Paz; Pruenster, Monika; Chu, Chung-Ching; Lombardi, Giovanna; Halsey, Christina; McInnes, Iain B.; Liew, Foo Y.; Nibbs, Robert J. B.; Graham, Gerard J.

doi:10.4049/jimmunol.181.11.8170-a

Cited by 55 publications

(78 citation statements)

References 49 publications

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“…In agreement with recent studies in mice, 11,12) the patient monocyte QPCR data also demonstrated expression of D6 on monocytes, although at relatively low levels. Intriguingly, as shown in Figure 3, Chemokine Decoy Receptor D6 transcript levels were lower in the intermediate monocytes of STEMI patients with diabetes compared to STEMI patients without diabetes (0.25 ± 0.13 versus 0.46 ± 0.16, P < 0.001) and no statistical significance was observed in the other two subsets of monocytes between the STEMI patients with or without diabetes.…”

Section: Resultssupporting

confidence: 78%

Intermediate Monocytes Lead to Enhanced Myocardial Remodelling in STEMI Patients With Diabetes

Zhang

2015

Int. Heart J.

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SummaryThis study aimed to evaluate the potential associations of intermediate monocytes (CD14 ++ CD16 + ) with myocardial remodelling in ST segment elevation myocardial infarction (STEMI) patients with diabetes.A total of 67 STEMI patients with diabetes were enrolled. The control group consisted of 65 STEMI patients without diabetes. All patients received emergency medical services for reperfusion therapy in less than 12 hours after onset of AMI. Blinded to patient clinical characteristics, monocyte subset analysis was performed using flow cytometry immediately after admission. mRNA of Chemokine Decoy Receptor D6 in each subset of monocytes was validated by Q-PCR. Expression of CCL2 in patient plasma was determined with an Elisa kit. Infarct size and left ventricular ejection fraction (LVEF) were measured using 3-dimensional echocardiography 3 days and 6 months after AMI. The incidences of recurrent cardiovascular events and death in each group were measured using the Kaplan-Meier estimator in follow-up during the next 24 months. Cox proportional-hazard models were further used to analyze the relationship of monocyte cell counts and event-free survival after adjusting for confounding factors.The number of circulating intermediate monocytes was significantly correlated with LVEF% and infarct size (r = -0.32; P = 0.008; r = 0.57, P < 0.001) in STEMI patients with diabetes compared with those without diabetes 6 months after AMI. Chemokine Decoy Receptor D6 transcript levels were lower in intermediate monocytes of STEMI patients with diabetes compared to the subsets in STEMI patients without diabetes (P < 0.001). Higher levels of CCL2 (pg/mL) were observed in STEMI patients with diabetes compared to STEMI patients without diabetes (P < 0.001). During a mean follow-up period of 24 ± 1 month, recurrent cardiovascular events or death occurred in 23 patients belonging to the STEMI with diabetes group and 10 belonging to the control group. Univariate Kaplan-Meier analysis revealed that counts of the intermediate monocytes according to median showed statistical significance in STEMI patients with diabetes (P = 0.010). After full adjustment for confounding factors, the cells were found to remain independently related to recurrent cardiovascular events or death in this group (P = 0.004, 95% CI: 1.62-12.49).Intermediate monocytes were associated with LV remodelling in STEMI patients with diabetes. The cells were predictive for recurrent cardiovascular events or death in these patients. A low level of D6 mRNA in the intermediate monocytes of STEMI patients with diabetes and high level of CCL2 in these patients may partially explain the causality. (Int Heart J 2015; 56: 22-28)

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Section: Resultssupporting

confidence: 78%

Intermediate Monocytes Lead to Enhanced Myocardial Remodelling in STEMI Patients With Diabetes

Zhang

2015

Int. Heart J.

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“…We have demonstrated that GATA1 is a physiological regulator of D6 expression [75] using mice with a conditional deletion in GATA1 [78]. In DC of these mice, the knockdown of GATA1 is associated with a transcriptional switch-off of D6 expression confirming a role for GATA1 in the regulation of D6 expression.…”

Section: Regulation Of D6 Expressionmentioning

confidence: 81%

“…As mentioned above such a role is unlikely to be filled by LECexpressed D6. We have now characterised the expression of D6 by leukocytes and it is apparent from this analysis that the role of leukocytes as vehicles for D6 function may not be as straightforward as we had initially appreciated [75,76]. …”

Section: D6 Expression By Leukocytesmentioning

confidence: 99%

D6 and the atypical chemokine receptor family: Novel regulators of immune and inflammatory processes

2009

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Chemokines are key regulators of leukocyte migration and play important roles in a number of physiological and pathological immune and inflammatory contexts. In addition to the classical signalling chemokine receptors there has emerged, recently, a new subclass of atypical chemokine receptors. This subfamily is characterised by an apparent lack of signalling and, in some cases, by an ability to internalise and degrade chemokine ligands. This review describes the family of atypical chemokine receptors with particular emphasis on the D6 receptor. The in vitro and in vivo biology of D6 is described, which indicates that D6 is active as a scavenger of inflammatory CC-chemokines and appears to play essential roles in the regulation of inflammatory responses.Key words: Chemokines . Immune regulation . Inflammation IntroductionThe movement of leukocytes during immune and inflammatory responses is a carefully orchestrated process that ensures coordinated cellular migration in response to physiological and pathological cues. Prominent amongst the regulators of leukocyte movement are the members of the chemokine family [1]. Chemokines are small proteins (8-12 kDa) and membership of the chemokine family is defined on the basis of the presence of variations on a conserved cysteine motif in the mature section of the proteins. Chemokines can be assigned to one of four subfamilies according to the specific nature of this motif. The majority of chemokines have four cysteines with 28 chemokines being assigned to the CC family (so-called because of the juxtaposition of the first two cysteine residues) and 16 being assigned to the CXC family (which possess a single variable amino acid between the first two cysteines). The two smaller subfamilies are represented by single members and are the CX3C family (three amino acids between the first two cyteines) and the XC family, which lacks the first and third cyteines seen in the other family members. Much confusion arose in the mid-1990s due to the complex and variable nomenclature used to refer to chemokines. For this reason a systematic nomenclature system has been adopted, which refers to the chemokines as ligands of each of the subfamilies and numbers them according to when their sequences were first deposited in the Genbank databases [2]. Thus, CCL1 is the first CC chemokine to be identified and CCL28 the most recent. Chemokines and their roles in leukocyte migrationFunctionally, chemokines are known to be pleiotropic. However, their main role is in the regulation of leukocyte migration. In this context we can define chemokines as being either homeostatic/ constitutive or inflammatory according to the contexts in which they function [2,3]. Homeostatic chemokinesThe homeostatic chemokines are important for the regulation of basal leukocyte trafficking and regulate processes such as the Mini-Reviewtissue-specific migration of T cells and the homing of DC to draining lymph nodes [4][5][6]. In combination with adhesion molecules, the homeostatic chemokines can form part of a very spec...

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“…D6, the best described chemokine decoy receptor (6), is a constitutively internalizing receptor expressed by lymphatic endothelial cells (11), trophoblast cells (12), and, at lower levels, some leukocyte subsets (13). D6 selectively recognizes and degrades most inflammatory CC chemokine agonists of CCR1 to CCR5 (10).…”

mentioning

confidence: 99%

Recognition Versus Adaptive Up-regulation and Degradation of CC Chemokines by the Chemokine Decoy Receptor D6 Are Determined by Their N-terminal Sequence

Savino

Borroni

Torres

et al. 2009

Journal of Biological Chemistry

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The chemokine decoy receptor D6 controls inflammatory responses by selective recognition and degradation of most CCR1 to CCR5 agonistic ligands. CCL14 is a homeostatic chemokine present at high concentrations in the serum with a weak agonist activity on CCR1. Under inflammatory conditions, plasmin and UPA-mediated truncation of 8 amino acids generates the potent CCR1/CCR3/CCR5 isoform CCL14(9 -74), which is further processed and inactivated by dipeptidyl peptidase IV/CD26 that generates CCL14(11-74). Here we report that D6 efficiently binds both CCL14 and its truncated isoforms. Like other D6 ligands, the biologically active CCL14(9 -74) induces adaptive up-regulation of D6 expression on the cell membrane and is rapidly and efficiently degraded. In contrast, the D6-mediated degradation of the biologically inactive isoforms CCL14(1-74) and CCL14(11-74) is very inefficient. Thus, D6 cooperates with CD26 in the negative regulation of CCL14 by the selective degradation of its biologically active isoform. Analysis of a panel of CC chemokines and their truncated isoforms revealed that D6-mediated chemokine degradation does not correlate with binding affinity. Conversely, degradation efficiency is positively correlated with D6 adaptive up-regulation. Sequence analysis indicated that a proline residue in position 2 of D6 ligands is dispensable for binding but crucial for D6 adaptive up-regulation and efficient degradation.

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Hemopoietic cell expression of the chemokine decoy receptor D6 is dynamic and regulated by GATA1

Abstract: This information is current as by GATA1 decoy receptor D6 is dynamic and regulated Hemopoietic cell expression of the chemokine

Cited by 55 publications

References 49 publications

Intermediate Monocytes Lead to Enhanced Myocardial Remodelling in STEMI Patients With Diabetes

Intermediate Monocytes Lead to Enhanced Myocardial Remodelling in STEMI Patients With Diabetes

D6 and the atypical chemokine receptor family: Novel regulators of immune and inflammatory processes

Recognition Versus Adaptive Up-regulation and Degradation of CC Chemokines by the Chemokine Decoy Receptor D6 Are Determined by Their N-terminal Sequence

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