Background and Aim. Post-infarction chemokine and cytokine secretion orchestrates the orderly influx of pro-inflammatory and pro-reparative immune cell subpopulations. Post-translational regulation of chemokine / cytokine signaling occurs via ectodomain shedding by a disintegrin and metalloproteases (ADAMs). Recently, we have identified a novel cardiomyocyte-specific ADAM10 / CX3CL1 signaling axis to regulate neutrophil migration early after myocardial infarction (MI). The CX3CL1 receptor of CX3CR1, however, is mainly described as marker protein for monocytes and macrophages. To clarify the role of this axis in neutrophil heart tissue infiltration, we here investigate CX3CL1 / CX3CR1 dynamics after infarction.

Methods and Results. CX3CL1 is upregulated in heart tissue biopsies of patients with ischemic cardiomyopathy and after LAD-ligation in mice with highest CX3CL1 expression in cardiomyocytes. Cultured cardiomyocytes subjected to hypoxia elevate ADAM10-dirven CX3CL1 secretion which specifically drives neutrophil but not macrophage chemotaxis. Similarly, CX3CL1 plasma levels increase rapidly after experimental infarction in mice and maintain increased until day 7 after infarction. Flowcytometric analysis of sham-operated revealed that the CX3CL1 receptor CX3CR1 is mostly expressed in bone marrow and heart tissue-derived monocytes and macrophages while only a minor population of neutrophils expressed the receptor. However, upon MI, the percentage of CX3CR1+ neutrophils in the ischemic area increases significantly, while bone marrow-derived neutrophils keep CX3CR1 expression at basal levels.

Conclusion. Our data suggest that cardiomyocyte-derived CX3CL1 specifically regulates neutrophil but not monocyte and macrophage migration after hypoxia and myocardial infarction. In addition, our results indicate an infarct-induced phenotypic switch to increased CX3CR1 expression in infiltrating neutrophils, which may be essential for migration into the infarcted tissue. To gain further insights into the role of this axis after MI, future experiments will assess the spatiotemporal kinetics of CX3CL1 / CX3CR1 binding in cardiac tissue and CX3CR1 dynamics in neutrophils after pro-inflammatory stimulation.