| First Author | Grisanti LA | Year | 2016 |
| Journal | Proc Natl Acad Sci U S A | Volume | 113 |
| Issue | 52 | Pages | 15126-15131 |
| PubMed ID | 27956622 | Mgi Jnum | J:239064 |
| Mgi Id | MGI:5824908 | Doi | 10.1073/pnas.1611023114 |
| Citation | Grisanti LA, et al. (2016) beta2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury. Proc Natl Acad Sci U S A 113(52):15126-15131 |
| abstractText | Following cardiac injury, early immune cell responses are essential for initiating cardiac remodeling and tissue repair. We previously demonstrated the importance of beta2-adrenergic receptors (beta2ARs) 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 beta2ARs 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 beta2AR knockout (KO) bone marrow (BM), both of which were rescued by beta2AR 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 beta2AR deletion. Converse to beta2AR ablation, beta2AR stimulation increased CCR2 expression and migratory responsiveness to CCL2 in BM. Mechanistically, G protein-dependent beta2AR signaling was dispensable for these effects, whereas beta-arrestin2-biased beta2AR 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 beta2AR stimulation in both murine BM and human monocytes. Finally, reconstitution of beta2ARKO BM with rescued expression of a beta-arrestin-biased beta2AR in vivo restored BM CCR2 expression as well as cardiac leukocyte infiltration following MI. These results demonstrate the critical role of beta-arrestin2/AP-1-dependent beta2AR signaling in the regulation of CCR2 expression and recruitment of leukocytes to the heart following injury. |
