The chemokine decoy receptor D6 prevents excessive inflammation and adverse ventricular remodeling after myocardial infarction.
OBJECTIVE
Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and overwhelming infiltration of innate immune cells has been shown to promote adverse remodeling and cardiac rupture. Recruitment of inflammatory cells in the ischemic heart depends highly on the family of CC-chemokines and their receptors. Here, we hypothesized that the chemokine decoy receptor D6, which specifically binds and scavenges inflammatory CC-chemokines, might limit inflammation and adverse cardiac remodeling after infarction.


RESULTS
D6 was expressed in human and murine infarcted myocardium. In a murine model of myocardial infarction, D6 deficiency led to increased chemokine (C-C motif) ligand 2 and chemokine (C-C motif) ligand 3 levels in the ischemic heart. D6-deficient (D6(-/-)) infarcts displayed increased infiltration of pathogenic neutrophils and Ly6Chi monocytes, associated with strong matrix metalloproteinase-9 and matrix metalloproteinase-2 activities in the ischemic heart. D6(-/-) mice were cardiac rupture prone after myocardial infarction, and functional analysis revealed that D6(-/-) hearts had features of adverse remodeling with left ventricle dilation and reduced ejection fraction. Bone marrow chimera experiments showed that leukocyte-borne D6 had no role in this setting, and that leukocyte-specific chemokine (C-C motif) receptor 2 deficiency rescued the adverse phenotype observed in D6(-/-) mice.


CONCLUSIONS
We show for the first time that the chemokine decoy receptor D6 limits CC-chemokine-dependent pathogenic inflammation and is required for adequate cardiac remodeling after myocardial infarction.
Université Paris Descartes, INSERM UMR-S970, Paris Cardiovascular Research Center, Hôpital Européen Georges Pompidou. Paris, France.
Clément
C
Cochain
Constance
C
Auvynet
Lucie
L
Poupel
José
J
Vilar
Edouard
E
Dumeau
Adèle
A
Richart
Alice
A
Récalde
Yasmine
Y
Zouggari
Kiave Yune Ho Wang
KY
Yin
Patrick
P
Bruneval
Gilles
G
Renault
Carmen
C
Marchiol
Philippe
P
Bonnin
Bernard
B
Lévy
Raffaella
R
Bonecchi
Massimo
M
Locati
Christophe
C
Combadière
Jean-Sébastien
JS
Silvestre
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3 / Q000378:metabolism; D002633:Chemotaxis; D004195:Disease Models, Animal; D005838:Genotype; D006342:Heart Rupture, Post-Infarction / Q000276:immunology / Q000473:pathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D009203:Myocardial Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology; D010641:Phenotype; D054447:Receptors, CCR10 / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013318:Stroke Volume; D014463:Ultrasonography; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D000097628:Chemokine Receptor D6
D000950:Antigens, Ly; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D018836:Inflammation Mediators; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D054447:Receptors, CCR10; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D000097628:Chemokine Receptor D6; C515709:Ackr2 protein, mouse; C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; C515335:Ccr2 protein, mouse; C526827:Ly6 protein, mouse; C522362:Mmp2 protein, mouse; C501830:Mmp9 protein, mouse