Beta2AR-Dependent Chemokine Receptor 2 Expression Regulates Leukocyte Recruitment to teh Heart Following Acute Injury.pdf (1.47 MB)
Beta2AR-Dependent Chemokine Receptor 2 Expression Regulates Leukocyte Recruitment to teh Heart Following Acute Injury.pdf
journal contribution
posted on 2019-03-08, 13:28 authored by Laurel A. Grisanti, Christopher J. Traynham, Ashley A. Repas, Erhe Gao, Walter J. Koch, Douglas G. TilleyFollowing 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 proteindependent
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.
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 proteindependent
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.
