Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype.
Acute myocardial infarction (MI) is the leading cause of mortality worldwide. Anti-inflammatory strategies to reduce neutrophil-driven acute post-MI injury have been shown to limit acute cardiac tissue damage. On the other hand, whether neutrophils are required for resolving post-MI inflammation and repair is unknown.



We show that neutrophil-depleted mice subjected to MI had worsened cardiac function, increased fibrosis, and progressively developed heart failure. Flow cytometry of blood, lymphoid organs and digested hearts revealed reduced numbers of Ly6Chigh monocytes in infarcts of neutrophil-depleted mice, whereas the number of macrophages increased, which was paralleled by reduced splenic Ly6Chigh monocyte mobilization but enhanced proliferation of cardiac macrophages. Macrophage subtype analysis revealed reduced cardiac expression of M1 markers, whereas M2 markers were increased in neutrophil-depleted mice. Surprisingly, we found reduced expression of phagocytosis receptor myeloid-epithelial-reproductive tyrosine kinase, a marker of reparative M2c macrophages which mediate clearance of apoptotic cells. In agreement with this finding, neutrophil-depleted mice had increased numbers of TUNEL-positive cells within infarcts. We identified neutrophil gelatinase-associated lipocalin (NGAL) in the neutrophil secretome as a key inducer of macrophages with high capacity to engulf apoptotic cells. The cardiac macrophage phenotype in neutrophil-depleted mice was restored by administration of neutrophil secretome or NGAL.



Neutrophils are crucially involved in cardiac repair after MI by polarizing macrophages towards a reparative phenotype. Therapeutic strategies to reduce acute neutrophil-driven inflammation after MI should be carefully balanced as they might interfere with the healing response and cardiac remodelling.
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, 80336 Munich, Germany.
Michael
M
Horckmans
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, 80336 Munich, Germany.
Larisa
L
Ring
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, 80336 Munich, Germany.
Johan
J
Duchene
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, 80336 Munich, Germany.|European Center of Excellence on Atherosclerosis, Hypertension and Dyslipidemia, G. d'Annunzio University, Chieti, Italy
Donato
D
Santovito
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, 80336 Munich, Germany.
Maximilian J
MJ
Schloss
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, 80336 Munich, Germany.|German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany|Department of Pathology, Amsterdam Medical Center (AMC), Amsterdam, The Netherlands
Maik
M
Drechsler
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, 80336 Munich, Germany.|German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
Christian
C
Weber
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, 80336 Munich, Germany.|German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany|Department of Pathology, Amsterdam Medical Center (AMC), Amsterdam, The Netherlands
Oliver
O
Soehnlein
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, 80336 Munich, Germany.|German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
Sabine
S
Steffens
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D004719:Endomyocardial Fibrosis / Q000209:etiology / Q000503:physiopathology; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology; D008026:Ligation; D000071068:Lipocalin-2 / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology; D009203:Myocardial Infarction / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009503:Neutropenia / Q000503:physiopathology; D009504:Neutrophils / Q000502:physiology*; D010641:Phenotype; D020257:Ventricular Remodeling / Q000502:physiology; D014945:Wound Healing / Q000502:physiology; D000076202:c-Mer Tyrosine Kinase / Q000378:metabolism
D000071068:Lipocalin-2; C490767:Mertk protein, mouse; D000076202:c-Mer Tyrosine Kinase