Macrophages and cardiac fibroblasts are the main producers of eotaxins and regulate eosinophil trafficking to the heart

Abstract

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.

Eosinophil deficiency promotes aberrant repair and adverse remodelling following acute myocardial infarction

“…Flow cytometric evaluation of Siglec-F + eosinophils in blood and single cell digests of left ventricle (Figure 2a) revealed that, in parallel with clinical observations, there was a peripheral blood eosinopenia after experimental MI (p=0.003; Figure 2b). In keeping with previous studies, 12 Siglec-F + Ly6G int eosinophils were rarely found in uninjured hearts ( Figure 2c). However, eosinophils were recruited to the heart from Day 1 post-MI, and particularly to the infarct zone, where their numbers peaked at Day 4 post-MI, during infarct repair ( Figure 2c).…”

Sca‐1+ cardiac fibroblasts promote development of heart failure

“…Thus, maintaining the right balance among different Th-directed cytokines is critical in preventing or limiting the progression of cardiac diseases to heart failure. We recently reported in a model of eosinophilic myocarditis that cardiac fibroblasts are potent producers of eotaxin 1 (CCL11), which is the main chemokine that regulates eosinophil trafficking to the heart [51]. In this study, we used the Sca-1 + cardiac fibroblasts from CCL2-mCherry reporter mice to demonstrate that the previous GM-CSF-and CCL2-expressing Sca-1 + cardiac fibroblasts are capable of switching to CCL11 producers after repolarization from Th17 to Th2 conditions.…”

Therapeutic effect of anti-IL-5 on eosinophilic myocarditis with large pericardial effusion

“…Granulocyte macrophage colony-stimulating factor and IL-3 also promote eosinophil maturation from myeloid precursors 8. Diny et al 9 showed that cytokines from the Th2 pathway (IL-4 and IL-13) can activate fibroblasts and macrophages in cardiomyocytes, which will further elevate eotaxin (CCL11 and CCL24) expression. Therefore, CCR3 expressed in eosinophils will accumulate in cardiomyocytes, which leads to damage of heart tissue.…”