期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：52
页码：15126-15131
DOI：10.1073/pnas.1611023114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe sympathetic nervous system influences various immune cell functions, in particular via {beta}2-adrenergic receptor ({beta}2AR) signaling. Although immune cell recruitment is critical for cardiac repair following ischemia, the impact of {beta}2AR on this process is unclear. We describe how immune cell-specific {beta}2AR depletion ablates chemokine receptor 2 (CCR2) expression and leukocyte recruitment to the heart postischemia. Reciprocally, {beta}2AR activation increases CCR2 expression and responsiveness in a {beta}-arrestin-dependent manner, and expression of a {beta}-arrestin-biased {beta}2AR in {beta}2AR-depleted immune cells restores CCR2 levels and leukocyte recruitment to the postischemic heart. These results highlight the potential utility of next-generation {beta}-arrestin-biased {beta}2AR ligands to selectively modulate leukocyte responsiveness, and suggest that {beta}-blockers, used commonly in peri/postischemic patients, may impact leukocyte-mediated repair mechanisms. Following cardiac injury, early immune cell responses are essential for initiating cardiac remodeling and tissue repair. We previously demonstrated the importance of {beta}2-adrenergic receptors ({beta}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 {beta}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 {beta}2AR knockout (KO) bone marrow (BM), both of which were rescued by {beta}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 {beta}2AR deletion. Converse to {beta}2AR ablation, {beta}2AR stimulation increased CCR2 expression and migratory responsiveness to CCL2 in BM. Mechanistically, G protein-dependent {beta}2AR signaling was dispensable for these effects, whereas {beta}-arrestin2-biased {beta}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 {beta}2AR stimulation in both murine BM and human monocytes. Finally, reconstitution of {beta}2ARKO BM with rescued expression of a {beta}-arrestin-biased {beta}2AR 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 {beta}2AR signaling in the regulation of CCR2 expression and recruitment of leukocytes to the heart following injury.
