The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions

The healing myocardium sequentially mobilizes two monocyte subsets with divergent and... Healing of myocardial infarction (MI) requires monocytes/macrophages. These mononuclear phagocytes likely degrade released macromolecules and aid in scavenging of dead cardiomyocytes, while mediating aspects of granulation tissue formation and remodeling. The mechanisms that orchestrate such divergent functions remain unknown. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we investigated whether distinct monocyte subsets contribute in specific ways to myocardial ischemic injury in mouse MI. We identify two distinct phases of monocyte participation after MI and propose a model that reconciles the divergent properties of these cells in healing. Infarcted hearts modulate their chemokine expression profile over time, and they sequentially and actively recruit Ly-6C hi and -6C lo monocytes via CCR2 and CX 3 CR1, respectively. Ly-6C hi monocytes dominate early (phase I) and exhibit phagocytic, proteolytic, and inflammatory functions. Ly-6C lo monocytes dominate later (phase II), have attenuated inflammatory properties, and express vascular–endothelial growth factor. Consequently, Ly-6C hi monocytes digest damaged tissue, whereas Ly-6C lo monocytes promote healing via myofibroblast accumulation, angiogenesis, and deposition of collagen. MI in atherosclerotic mice with chronic Ly-6C hi monocytosis results in impaired healing, underscoring the need for a balanced and coordinated response. These observations provide novel mechanistic insights into the cellular and molecular events that regulate the response to ischemic injury and identify new therapeutic targets that can influence healing and ventricular remodeling after MI. Footnotes Abbreviations used: apoE, apolipoprotein E; MI, myocardial infarction; PSR, picrosirius red; VEGF, vascular endothelial growth factor. M. Nahrendorf and F.K. Swirski contributed equally to this paper. Submitted: 3 May 2007 Accepted: 25 October 2007 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions

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Publisher
Rockefeller University Press
Copyright
© 2007 Rockefeller University Press
ISSN
0022-1007
eISSN
1540-9538
D.O.I.
10.1084/jem.20070885
Publisher site
See Article on Publisher Site

Abstract

Healing of myocardial infarction (MI) requires monocytes/macrophages. These mononuclear phagocytes likely degrade released macromolecules and aid in scavenging of dead cardiomyocytes, while mediating aspects of granulation tissue formation and remodeling. The mechanisms that orchestrate such divergent functions remain unknown. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we investigated whether distinct monocyte subsets contribute in specific ways to myocardial ischemic injury in mouse MI. We identify two distinct phases of monocyte participation after MI and propose a model that reconciles the divergent properties of these cells in healing. Infarcted hearts modulate their chemokine expression profile over time, and they sequentially and actively recruit Ly-6C hi and -6C lo monocytes via CCR2 and CX 3 CR1, respectively. Ly-6C hi monocytes dominate early (phase I) and exhibit phagocytic, proteolytic, and inflammatory functions. Ly-6C lo monocytes dominate later (phase II), have attenuated inflammatory properties, and express vascular–endothelial growth factor. Consequently, Ly-6C hi monocytes digest damaged tissue, whereas Ly-6C lo monocytes promote healing via myofibroblast accumulation, angiogenesis, and deposition of collagen. MI in atherosclerotic mice with chronic Ly-6C hi monocytosis results in impaired healing, underscoring the need for a balanced and coordinated response. These observations provide novel mechanistic insights into the cellular and molecular events that regulate the response to ischemic injury and identify new therapeutic targets that can influence healing and ventricular remodeling after MI. Footnotes Abbreviations used: apoE, apolipoprotein E; MI, myocardial infarction; PSR, picrosirius red; VEGF, vascular endothelial growth factor. M. Nahrendorf and F.K. Swirski contributed equally to this paper. Submitted: 3 May 2007 Accepted: 25 October 2007

Journal

The Journal of Experimental MedicineRockefeller University Press

Published: Nov 26, 2007

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