Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction.
BACKGROUND
Macrophages populate the steady-state myocardium. Previously, all macrophages were thought to arise from monocytes; however, it emerged that, in several organs, tissue-resident macrophages may self-maintain through local proliferation.


OBJECTIVE
Our aim was to study the contribution of monocytes to cardiac-resident macrophages in steady state, after macrophage depletion in CD11b(DTR/+) mice and in myocardial infarction.


RESULTS
Using in vivo fate mapping and flow cytometry, we estimated that during steady state the heart macrophage population turns over in ≈1 month. To explore the source of cardiac-resident macrophages, we joined the circulation of mice using parabiosis. After 6 weeks, we observed blood monocyte chimerism of 35.3±3.4%, whereas heart macrophages showed a much lower chimerism of 2.7±0.5% (P<0.01). Macrophages self-renewed locally through proliferation: 2.1±0.3% incorporated bromodeoxyuridine 2 hours after a single injection, and 13.7±1.4% heart macrophages stained positive for the cell cycle marker Ki-67. The cells likely participate in defense against infection, because we found them to ingest fluorescently labeled bacteria. In ischemic myocardium, we observed that tissue-resident macrophages died locally, whereas some also migrated to hematopoietic organs. If the steady state was perturbed by coronary ligation or diphtheria toxin-induced macrophage depletion in CD11b(DTR/+) mice, blood monocytes replenished heart macrophages. However, in the chronic phase after myocardial infarction, macrophages residing in the infarct were again independent from the blood monocyte pool, returning to the steady-state situation.


CONCLUSIONS
In this study, we show differential contribution of monocytes to heart macrophages during steady state, after macrophage depletion or in the acute and chronic phase after myocardial infarction. We found that macrophages participate in the immunosurveillance of myocardial tissue. These data correspond with previous studies on tissue-resident macrophages and raise important questions on the fate and function of macrophages during the development of heart failure.
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Timo
T
Heidt
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Gabriel
G
Courties
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Partha
P
Dutta
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Hendrik B
HB
Sager
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Matt
M
Sebas
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Yoshiko
Y
Iwamoto
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Yuan
Y
Sun
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Nicolas
N
Da Silva
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Peter
P
Panizzi
Anja M
AM
van der Laan
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Anja M
AM
van der Lahn
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Filip K
FK
Swirski
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Ralph
R
Weissleder
From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.). mnahrendorf@mgh.harvard.edu.
Matthias
M
Nahrendorf
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D000073883:CX3C Chemokine Receptor 1; D002455:Cell Division; D004167:Diphtheria Toxin / Q000633:toxicity; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D009203:Myocardial Infarction / Q000276:immunology* / Q000473:pathology; D017202:Myocardial Ischemia / Q000276:immunology* / Q000473:pathology; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D010227:Parabiosis; D010587:Phagocytosis; D011828:Radiation Chimera; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology
D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D004167:Diphtheria Toxin; D019707:Receptors, Chemokine
heart; macrophages; monocytes; myocardial infarction