Gopalkrishna Sreejit1,2, Ahmed Abdel-Latif3, Baskaran Athmanathan1,2, Andrew J Murphy4,5, Prabhakara R Nagareddy1,2, Rahul Annabathula3, Ashish Dhyani2, Sunil K Noothi2,6, Gregory A Quaife-Ryan7,8, Annas Al-Sharea4, Gerard Pernes4, Dragana Dragoljevic4, Hind Lal9, Kate Schroder10,11, Beatriz Y Hanaoka12,9, Chander Raman9, Maria B Grant6, James E Hudson8, Susan S Smyth3, Enzo R Porrello13,14. 1. Department of Surgery (G.S., B.A., P.R.N.), Ohio State University Wexner Medical Center, Columbus. 2. Departments of Pathology (G.S., B.A., A.D., S.K.N., P.R.N.), University of Alabama at Birmingham. 3. Department of Medicine, University of Kentucky, Lexington (A.A.-L., R.A., S.S.S.). 4. Baker Heart and Diabetes Institute, Division of Immunometabolism, Melbourne, Australia (A.A.-S., G.P., D.D., A.J.M.). 5. Department of Immunology, Monash University, Melbourne, Australia (A.J.M.). 6. Ophthalmology and Visual Sciences (S.K.N., M.B.G.), University of Alabama at Birmingham. 7. School of Biomedical Sciences (G.A.Q.-R.), University of Queensland, St. Lucia, Australia. 8. QIMR Berghofer Medical Research Institute, Brisbane, Australia (G.A.Q.-R., J.E.H.). 9. Medicine (H.L., B.Y.H., C.R.), University of Alabama at Birmingham. 10. Institute for Molecular Bioscience (IMB) (K.S.), University of Queensland, St. Lucia, Australia. 11. IMB Centre for Inflammation and Disease Research (K.S.), University of Queensland, St. Lucia, Australia. 12. Department of Medicine (B.Y.H.), Ohio State University Wexner Medical Center, Columbus. 13. Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia (E.R.P.). 14. Department of Physiology, School of Biomedical Sciences, University of Melbourne, Australia (E.R.P.).
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 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 the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI. RESULTS: Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease 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 after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.
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 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 the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI. RESULTS: Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease 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 after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.
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