S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll-like receptor 4.
Members of the S100 protein family have been reported to function as endogenous danger signals (alarmins) playing an active role in tissue inflammation and repair when released from necrotic cells. Here, we investigated the role of S100A1, the S100 isoform with highest abundance in cardiomyocytes, when released from damaged cardiomyocytes during myocardial infarction (MI). Patients with acute MI showed significantly increased S100A1 serum levels. Experimental MI in mice induced comparable S100A1 release. S100A1 internalization was observed in cardiac fibroblasts (CFs) adjacent to damaged cardiomyocytes. In vitro analyses revealed exclusive S100A1 endocytosis by CFs, followed by Toll-like receptor 4 (TLR4)-dependent activation of MAP kinases and NF-κB. CFs exposed to S100A1 assumed an immunomodulatory and anti-fibrotic phenotype characterized i.e. by enhanced intercellular adhesion molecule-1 (ICAM1) and decreased collagen levels. In mice, intracardiac S100A1 injection recapitulated these transcriptional changes. Moreover, antibody-mediated neutralization of S100A1 enlarged infarct size and worsened left ventricular functional performance post-MI. Our study demonstrates alarmin properties for S100A1 from necrotic cardiomyocytes. However, the potentially beneficial role of extracellular S100A1 in MI-related inflammation and repair warrants further investigation.
Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany.
David
D
Rohde
Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany.
Christoph
C
Schön
Institute of Molecular Medicine and Cell Research, Freiburg University, Freiburg, Germany German Consortium for Translational Cancer Research (DKTK), Partner site Freiburg German Cancer Research Center (DKFZ), Heidelberg, Germany.
Melanie
M
Boerries
Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany.
Ieva
I
Didrihsone
Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany.
Julia
J
Ritterhoff
Division for Microbiology and Hygiene, Department of Infectious Diseases, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany.
Katharina F
KF
Kubatzky
Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany.
Mirko
M
Völkers
Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany.
Nicole
N
Herzog
Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany.
Mona
M
Mähler
Division of Cardiology, Department of Medicine, Keenan Research Centre Li Ka Shing Knowledge Institute St. Michael's Hospital University of Toronto, Ontario, Canada.
James N
JN
Tsoporis
Division of Cardiology, Department of Medicine, Keenan Research Centre Li Ka Shing Knowledge Institute St. Michael's Hospital University of Toronto, Ontario, Canada.
Thomas G
TG
Parker
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Björn
B
Linke
Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany.
Evangelos
E
Giannitsis
Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Erhe
E
Gao
Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Karsten
K
Peppel
Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany German Centre for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim Heidelberg University Hospital Heidelberg University, Heidelberg, Germany.
Hugo A
HA
Katus
Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA German Centre for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim Heidelberg University Hospital Heidelberg University, Heidelberg, Germany patrick.most@med.uni-heidelberg.de.
Patrick
P
Most
D000818:Animals; D004705:Endocytosis; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D009203:Myocardial Infarction / Q000097:blood / Q000276:immunology / Q000473:pathology*; D009206:Myocardium / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000276:immunology / Q000473:pathology*; D016328:NF-kappa B / Q000276:immunology; D009418:S100 Proteins / Q000097:blood* / Q000276:immunology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology*
D016328:NF-kappa B; D009418:S100 Proteins; C110294:S100A1 protein; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020928:Mitogen-Activated Protein Kinases
S100A1; Toll‐like receptors (TLRs); alarmin; cardiac fibroblast; damage‐associated molecular pattern (DAMP)