Macrophages and cardiac fibroblasts are the main producers of eotaxins and regulate eosinophil trafficking to the heart.
Cardiac manifestations are a major cause of morbidity and mortality in patients with eosinophil-associated diseases. Eosinophils are thought to play a pathogenic role in myocarditis. We investigated the pathways that recruit eosinophils to the heart using a model of eosinophilic myocarditis, in which experimental autoimmune myocarditis (EAM) is induced in IFNγ-/-IL-17A-/-mice. Two conditions are necessary for efficient eosinophil trafficking to the heart: high eotaxin (CCL11, CCL24) expression in the heart and expression of the eotaxin receptor CCR3 by eosinophils. We identified cardiac fibroblasts as the source of CCL11 in the heart interstitium. CCL24 is produced by F4/80+macrophages localized at inflammatory foci in the heart. Expression of CCL11 and CCL24 is controlled by Th2 cytokines, IL-4 and IL-13. To determine the relevance of this pathway in humans, we analyzed endomyocardial biopsy samples from myocarditis patients. Expression of CCL11 and CCL26 was significantly increased in eosinophilic myocarditis compared to chronic lymphocytic myocarditis and positively correlated with the number of eosinophils. Thus, eosinophil trafficking to the heart is dependent on the eotaxin-CCR3 pathway in a mouse model of EAM and associated with cardiac eotaxin expression in patients with eosinophilic myocarditis. Blocking this pathway may prevent eosinophil-mediated cardiac damage.
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
Nicola L
NL
Diny
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
Xuezhou
X
Hou
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jobert G
JG
Barin
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Guobao
G
Chen
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Monica V
MV
Talor
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Julie
J
Schaub
Department of Medicine Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Stuart D
SD
Russell
Abteilung für Molekulare Pathologie, Eberhard Karls Universität Tübingen, Tübingen, Germany.
Karin
K
Klingel
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Noel R
NR
Rose
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Daniela
D
Čiháková
D000328:Adult; D000368:Aged; D000818:Animals; D024722:Cardiac Myosins / Q000276:immunology; D002465:Cell Movement; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000378:metabolism*; D054423:Chemokine CCL24 / Q000378:metabolism*; D004804:Eosinophils / Q000276:immunology*; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009205:Myocarditis / Q000276:immunology*; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D020721:Nervous System Autoimmune Disease, Experimental / Q000276:immunology*; D054397:Receptors, CCR3 / Q000235:genetics; D058408:Th1-Th2 Balance
C515457:Ccl11 protein, mouse; C515485:Ccl24 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D054397:Receptors, CCR3; D007371:Interferon-gamma; D024722:Cardiac Myosins
Cardiomyopathy; Cell trafficking; Chemokines; Eosinophils; Eotaxins; Experimental autoimmune myocarditis; Inflammation