?2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury.

ABSTRACT: Following cardiac injury, early immune cell responses are essential for initiating cardiac remodeling and tissue repair. We previously demonstrated the importance of ?2-adrenergic receptors (?2ARs) in the regulation of immune cell localization following acute cardiac injury, with deficient leukocyte infiltration into the damaged heart. The purpose of this study was to investigate the mechanism by which immune cell-expressed ?2ARs regulate leukocyte recruitment to the heart following acute cardiac injury. Chemokine receptor 2 (CCR2) expression and responsiveness to C-C motif chemokine ligand 2 (CCL2)-mediated migration were abolished in ?2AR knockout (KO) bone marrow (BM), both of which were rescued by ?2AR reexpression. 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 recruitment to the heart following myocardial infarction (MI) observed in mice with immune cell-specific ?2AR deletion. Converse to ?2AR ablation, ?2AR stimulation increased CCR2 expression and migratory responsiveness to CCL2 in BM. Mechanistically, G protein-dependent ?2AR signaling was dispensable for these effects, whereas ?-arrestin2-biased ?2AR signaling was required for the regulation of CCR2 expression. Additionally, activator protein 1 (AP-1) was shown to be essential in mediating CCR2 expression in response to ?2AR stimulation in both murine BM and human monocytes. Finally, reconstitution of ?2ARKO BM with rescued expression of a ?-arrestin-biased ?2AR in vivo restored BM CCR2 expression as well as cardiac leukocyte infiltration following MI. These results demonstrate the critical role of ?-arrestin2/AP-1-dependent ?2AR signaling in the regulation of CCR2 expression and recruitment of leukocytes to the heart following injury.

SUBMITTER: Grisanti LA 

PROVIDER: S-EPMC5206565 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature