The Healing Myocardium Sequentially Mobilizes Two Monocyte Subsets with Divergent and Complementary Functions

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2007 Nov 21

PMID 18025128

Citations 1153

Authors

Matthias Nahrendorf

Filip K Swirski

Elena Aikawa

Lars Stangenberg

Thomas Wurdinger

Jose-Luiz Figueiredo

Peter Libby

Ralph Weissleder

Mikael J Pittet

Affiliations

Soon will be listed here.

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.

Citing Articles

Exploring the role of mitochondrial antiviral signaling protein in cardiac diseases.

Qi Y, Yin J, Xia W, Yang S Front Immunol. 2025; 16:1540774.

PMID: 40040697 PMC: 11876050. DOI: 10.3389/fimmu.2025.1540774.

A Mathematical Exploration of the Effects of Ischemia-Reperfusion Injury After a Myocardial Infarction.

Lafci Buyukkahraman M, Chen H, Chen-Charpentier B, Liao J, Kojouharov H Bioengineering (Basel). 2025; 12(2).

PMID: 40001696 PMC: 11851514. DOI: 10.3390/bioengineering12020177.

Emerging Role of Macrophage-Fibroblast Interactions in Cardiac Homeostasis and Remodeling.

Zhang X, Li Q, Tang T, Cheng X JACC Basic Transl Sci. 2025; 10(1):113-127.

PMID: 39958468 PMC: 11830265. DOI: 10.1016/j.jacbts.2024.06.003.

Intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damage.

Hanna M, Akabawy A, Khalifa M, Elbaset M, Imam R, Seddiek H Front Physiol. 2025; 16:1430946.

PMID: 39949667 PMC: 11821637. DOI: 10.3389/fphys.2025.1430946.

Effects of injury size on local and systemic immune cell dynamics in volumetric muscle loss.

Whitaker R, Sung S, Tylek T, Risser G, OBrien E, Chua P NPJ Regen Med. 2025; 10(1):9.

PMID: 39939310 PMC: 11822203. DOI: 10.1038/s41536-025-00397-z.

References

Tsou C, Peters W, Si Y, Slaymaker S, Aslanian A, Weisberg S . Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest. 2007; 117(4):902-9. PMC: 1810572. DOI: 10.1172/JCI29919. View

Pfeffer M, Pfeffer J . Ventricular enlargement and reduced survival after myocardial infarction. Circulation. 1987; 75(5 Pt 2):IV93-7. View

Pfeffer M, Braunwald E . Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990; 81(4):1161-72. DOI: 10.1161/01.cir.81.4.1161. View

Libby P . Inflammation in atherosclerosis. Nature. 2002; 420(6917):868-74. DOI: 10.1038/nature01323. View

Morimoto H, Takahashi M, Izawa A, Ise H, Hongo M, Kolattukudy P . Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction. Circ Res. 2006; 99(8):891-9. DOI: 10.1161/01.RES.0000246113.82111.2d. View

Blankesteijn W, Creemers E, Lutgens E, Cleutjens J, Daemen M, Smits J . Dynamics of cardiac wound healing following myocardial infarction: observations in genetically altered mice. Acta Physiol Scand. 2001; 173(1):75-82. DOI: 10.1046/j.1365-201X.2001.00887.x. View

Gordon S . Macrophage heterogeneity and tissue lipids. J Clin Invest. 2007; 117(1):89-93. PMC: 1716225. DOI: 10.1172/JCI30992. View

Sutton M, Sharpe N . Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000; 101(25):2981-8. DOI: 10.1161/01.cir.101.25.2981. View

Serbina N, Pamer E . Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006; 7(3):311-7. DOI: 10.1038/ni1309. View

10.

Mariani M, Fetiveau R, Rossetti E, Poli A, Poletti F, Vandoni P . Significance of total and differential leucocyte count in patients with acute myocardial infarction treated with primary coronary angioplasty. Eur Heart J. 2006; 27(21):2511-5. DOI: 10.1093/eurheartj/ehl191. View

11.

Cleutjens J, Blankesteijn W, Daemen M, Smits J . The infarcted myocardium: simply dead tissue, or a lively target for therapeutic interventions. Cardiovasc Res. 2000; 44(2):232-41. DOI: 10.1016/s0008-6363(99)00212-6. View

12.

Swirski F, Pittet M, Kircher M, Aikawa E, Jaffer F, Libby P . Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci U S A. 2006; 103(27):10340-10345. PMC: 1502459. DOI: 10.1073/pnas.0604260103. View

13.

Plump A, Smith J, Hayek T, Aalto-Setala K, Walsh A, Verstuyft J . Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992; 71(2):343-53. DOI: 10.1016/0092-8674(92)90362-g. View

14.

Whittaker P, Boughner D, Kloner R . Role of collagen in acute myocardial infarct expansion. Circulation. 1991; 84(5):2123-34. DOI: 10.1161/01.cir.84.5.2123. View

15.

Maekawa Y, Anzai T, Yoshikawa T, Sugano Y, Mahara K, Kohno T . Effect of granulocyte-macrophage colony-stimulating factor inducer on left ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol. 2004; 44(7):1510-20. DOI: 10.1016/j.jacc.2004.05.083. View

16.

Barron H, Cannon C, Murphy S, Braunwald E, Gibson C . Association between white blood cell count, epicardial blood flow, myocardial perfusion, and clinical outcomes in the setting of acute myocardial infarction: a thrombolysis in myocardial infarction 10 substudy. Circulation. 2000; 102(19):2329-34. DOI: 10.1161/01.cir.102.19.2329. View

17.

Lumeng C, Bodzin J, Saltiel A . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007; 117(1):175-84. PMC: 1716210. DOI: 10.1172/JCI29881. View

18.

Kumar D, Hacker T, Buck J, Whitesell L, Kaji E, Douglas P . Distinct mouse coronary anatomy and myocardial infarction consequent to ligation. Coron Artery Dis. 2005; 16(1):41-4. DOI: 10.1097/00019501-200502000-00008. View

19.

Geissmann F, Jung S, Littman D . Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003; 19(1):71-82. DOI: 10.1016/s1074-7613(03)00174-2. View

20.

Kirtane A, Bui A, Murphy S, Barron H, Gibson C . Association of peripheral neutrophilia with adverse angiographic outcomes in ST-elevation myocardial infarction. Am J Cardiol. 2004; 93(5):532-6. DOI: 10.1016/j.amjcard.2003.11.013. View