title: β2-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 β2-adrenergic receptors (β2ARs) 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 β2ARs 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 β2AR knockout (KO) bone marrow (BM), both of which were rescued by β2AR 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 β2AR deletion. Converse to β2AR ablation, β2AR stimulation increased CCR2 expression and migratory responsiveness to CCL2 in BM. Mechanistically, G protein-dependent β2AR signaling was dispensable for these effects, whereas β-arrestin2-biased β2AR 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 β2AR stimulation in both murine BM and human monocytes. Finally, reconstitution of β2ARKO BM with rescued expression of a β-arrestin-biased β2AR in vivo restored BM CCR2 expression as well as cardiac leukocyte infiltration following MI. These results demonstrate the critical role of β-arrestin2/AP-1-dependent β2AR signaling in the regulation of CCR2 expression and recruitment of leukocytes to the heart following injury.
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Grisanti
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Traynham
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Repas
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140 douglas.tilley@temple.edu.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism; D003331:Coronary Vessels / Q000473:pathology; D004452:Echocardiography; D006333:Heart Failure / Q000473:pathology; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology*; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D020556:Neutrophil Infiltration; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C515334:CCR2 protein, human; D018925:Chemokines; D011943:Receptors, Adrenergic, beta; D054390:Receptors, CCR2; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse
keywords: C-chemokine receptor 2; cardiac injury; leukocyte; β-arrestin; β2-adrenergic receptor