Beta2AR-Dependent Chemokine Receptor 2 Expression Regulates Leukocyte Recruitment to teh Heart Following Acute Injury.pdf

Following cardiac injury, early immune cell responses are essentialfor initiating cardiac remodeling and tissue repair. We previouslydemonstrated the importance of β2-adrenergic receptors (β2ARs)in the regulation of immune cell localization following acute cardiacinjury, with deficient leukocyte infiltration into the damagedheart. The purpose of this study was to investigate the mechanismby which immune cell-expressed β2ARs regulate leukocyte recruitmentto the heart following acute cardiac injury. Chemokine receptor2 (CCR2) expression and responsiveness to C-C motif chemokineligand 2 (CCL2)-mediated migration were abolished in β2AR knockout(KO) bone marrow (BM), both of which were rescued by β2ARreexpression. Chimeric mice lacking immune cell-specific CCR2 expression,as well as wild-type mice administered a CCR2 antagonist,recapitulated the loss of monocyte/macrophage and neutrophil recruitmentto the heart following myocardial infarction (MI) observedin mice with immune cell-specific β2AR deletion. Converseto β2AR ablation, β2AR stimulation increased CCR2 expression andmigratory responsiveness to CCL2 in BM. Mechanistically, G proteindependentβ2AR signaling was dispensable for these effects,whereas β-arrestin2–biased β2AR signaling was required for theregulation of CCR2 expression. Additionally, activator protein 1(AP-1) was shown to be essential in mediating CCR2 expressionin response to β2AR stimulation in both murine BM and humanmonocytes. Finally, reconstitution of β2ARKO BM with rescued expressionof a β-arrestin–biased β2AR in vivo restored BM CCR2 expressionas well as cardiac leukocyte infiltration following MI. Theseresults demonstrate the critical role of β-arrestin2/AP-1–dependentβ2AR signaling in the regulation of CCR2 expression and recruitmentof leukocytes to the heart following injury.