Beta2AR-Dependent Chemokine Receptor 2 Expression Regulates Leukocyte Recruitment to teh Heart Following Acute Injury.pdf Laurel A. Grisanti Christopher J. Traynham Ashley A. Repas Erhe Gao Walter J. Koch Douglas G. Tilley 10.25376/hra.7817954.v1 https://hra.figshare.com/articles/journal_contribution/Beta2AR-Dependent_Chemokine_Receptor_2_Expression_Regulates_Leukocyte_Recruitment_to_teh_Heart_Following_Acute_Injury_pdf/7817954 Following cardiac injury, early immune cell responses are essential<br>for initiating cardiac remodeling and tissue repair. We previously<br>demonstrated the importance of β2-adrenergic receptors (β2ARs)<br>in the regulation of immune cell localization following acute cardiac<br>injury, with deficient leukocyte infiltration into the damaged<br>heart. The purpose of this study was to investigate the mechanism<br>by which immune cell-expressed β2ARs regulate leukocyte recruitment<br>to the heart following acute cardiac injury. Chemokine receptor<br>2 (CCR2) expression and responsiveness to C-C motif chemokine<br>ligand 2 (CCL2)-mediated migration were abolished in β2AR knockout<br>(KO) bone marrow (BM), both of which were rescued by β2AR<br>reexpression. Chimeric mice lacking immune cell-specific CCR2 expression,<br>as well as wild-type mice administered a CCR2 antagonist,<br>recapitulated the loss of monocyte/macrophage and neutrophil recruitment<br>to the heart following myocardial infarction (MI) observed<br>in mice with immune cell-specific β2AR deletion. Converse<br>to β2AR ablation, β2AR stimulation increased CCR2 expression and<br>migratory responsiveness to CCL2 in BM. Mechanistically, G proteindependent<br>β2AR signaling was dispensable for these effects,<br>whereas β-arrestin2–biased β2AR signaling was required for the<br>regulation of CCR2 expression. Additionally, activator protein 1<br>(AP-1) was shown to be essential in mediating CCR2 expression<br>in response to β2AR stimulation in both murine BM and human<br>monocytes. Finally, reconstitution of β2ARKO BM with rescued expression<br>of a β-arrestin–biased β2AR in vivo restored BM CCR2 expression<br>as well as cardiac leukocyte infiltration following MI. These<br>results demonstrate the critical role of β-arrestin2/AP-1–dependent<br>β2AR signaling in the regulation of CCR2 expression and recruitment<br>of leukocytes to the heart following injury.<br> 2019-03-08 13:28:58 β2-adrenergic receptor agonists leukocyte C-chemikine receptor 2 cardiac injury β-arrestin Cardiology (incl. Cardiovascular Diseases)