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Circulation. 2020 Jan 16. doi: 10.1161/CIRCULATIONAHA.119.043833. [Epub ahead of print]

Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis Following Myocardial Infarction.

Author information

1
Department of Surgery, Ohio State University Wexner Medical Center, Columbus, OH; Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL.
2
Department of Medicine, University of Kentucky, Lexington, KY.
3
Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL.
4
Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL; Department of Ophthalmology and Visual Sciences, UAB, Birmingham, AL.
5
School of Biomedical Sciences, University of Queensland, St. Lucia, Australia; QIMR Berghofer Medical Research Institute, Brisbane, Australia.
6
Baker Heart and Diabetes Institute, Division of Immunometabolism, Melbourne, Australia.
7
Department of Medicine, UAB, Birmingham, AL.
8
Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, Australia.
9
Department of Medicine, UAB, Birmingham, AL; Department of Medicine, Ohio State University Wexner Medical Center, Columbus, OH.
10
Department of Ophthalmology and Visual Sciences, UAB, Birmingham, AL.
11
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
12
Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia; Department of Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, Australia.
13
Baker Heart and Diabetes Institute, Division of Immunometabolism, Melbourne, Australia; Department of Immunology, Monash University, Melbourne, Australia.

Abstract

Background: Myocardial infarction (MI) triggers myelopoiesis resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear. Methods: Using a mouse model of the permanent ligation of the left anterior descending (LAD) artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of acute inflammatory response and the underlying signaling pathways. Utilizing a combination of genetic and pharmacological strategies, we identified the sequalae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indices of neutrophilia with major adverse cardiovascular events (MACE) was studied in a cohort of acute MI patients. Results: Induction of MI resulted in a rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll Like Receptor (TLR) 4 and prime the Nod Like Receptor (NLR) family Pyrin Domain-Containing 3 (Nlrp3) inflammasome in naïve neutrophils and promote interleukin 1 (IL-1β) secretion. The released IL-1β interact with its receptor (Interleukin 1 Receptor Type 1, IL1R1) on hematopoietic stem and progenitor cells in the bone marrow (BM), and stimulate granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and its downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome (ACS), higher neutrophil count on admission and post-revascularization correlates positively with major adverse cardiovascular disease (CVD) outcomes. Conclusions: Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response following myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or its downstream mediators (e.g. Nlrp3, IL-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in ACS patients.

KEYWORDS:

Inflammasome; Myelopoiesis; Neutrophils; S100A8/A9; interleukin 1 beta

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