Neutrophil stunning by metoprolol reduces infarct size

The beta 1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients. The prevailing view has been that metoprolol acts mainly on cardiomyocytes. Here, we demonstrate that metoprolol reduces reperfusion injury by targeting the haematopoietic compartment. Metoprolol inhibits neutrophil migration in an ADRB1-dependent manner. Metoprolol acts during early phases of neutrophil recruitment by impairing structural and functional rearrangements needed for productive engagement of circulating platelets, resulting in erratic intravascular dynamics and blunted inflammation. Depletion of neutrophils, ablation of Adrb1 in haematopoietic cells, or blockade of PSGL-1, the receptor involved in neutrophil-platelet interactions, fully abrogated metoprolol's infarct-limiting effects. The association between neutrophil count and microvascular obstruction is abolished in metoprolol-treated AMI patients. Metoprolol inhibits neutrophil-platelet interactions in AMI patients by targeting neutrophils. Identification of the relevant role of ADRB1 in haematopoietic cells during acute injury and the protective role upon its modulation offers potential for developing new therapeutic strategies.European Regional Development Fund (ERDF/FEDER) PI10/02268 PI13/01979 RD12/0042/0054ERDF/FEDER SAF2015-65607-RFundacio La Marato-TV3 120/C/2015-20153032Severo Ochoa Center of Excellence (MINECO) SEV-2015-0505Pro-CNIC FoundationSpanish Ministry of Economy and Competitiveness (MINECO)Fundacion Interhospitalaria de Investigacion Cardiovascular (FIC)12.353 JCR (2017) Q1, 3/64 Multidisciplinary SciencesUE