Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis.
Monocytes (Mo) and macrophages (MΦ) are emerging therapeutic targets in malignant, cardiovascular, and autoimmune disorders. Targeting of Mo/MΦ and their effector functions without compromising innate immunity's critical defense mechanisms first requires addressing gaps in knowledge about the life cycle of these cells. Here we studied the source, tissue kinetics, and clearance of Mo/MΦ in murine myocardial infarction, a model of acute inflammation after ischemic injury. We found that a) Mo tissue residence time was surprisingly short (20 h); b) Mo recruitment rates were consistently high even days after initiation of inflammation; c) the sustained need of newly made Mo was fostered by extramedullary monocytopoiesis in the spleen; d) splenic monocytopoiesis was regulated by IL-1β; and e) the balance of cell recruitment and local death shifted during resolution of inflammation. Depending on the experimental approach, we measured a 24 h Mo/MΦ exit rate from infarct tissue between 5 and 13% of the tissue cell population. Exited cells were most numerous in the blood, liver, and spleen. Abrogation of extramedullary monocytopoiesis proved deleterious for infarct healing and accelerated the evolution of heart failure. We also detected rapid Mo kinetics in mice with stroke. These findings expand our knowledge of Mo/MΦ flux in acute inflammation and provide the groundwork for novel anti-inflammatory strategies for treating heart failure.
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston, MA 02114, USA.
Florian
F
Leuschner
Philipp J
PJ
Rauch
Takuya
T
Ueno
Rostic
R
Gorbatov
Brett
B
Marinelli
Won Woo
WW
Lee
Partha
P
Dutta
Ying
Y
Wei
Clinton
C
Robbins
Yoshiko
Y
Iwamoto
Brena
B
Sena
Aleksey
A
Chudnovskiy
Peter
P
Panizzi
Edmund
E
Keliher
John M
JM
Higgins
Peter
P
Libby
Michael A
MA
Moskowitz
Mikael J
MJ
Pittet
Filip K
FK
Swirski
Ralph
R
Weissleder
Matthias
M
Nahrendorf
D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006411:Hematopoiesis, Extramedullary; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology* / Q000502:physiology*; D022423:Myeloid Cells / Q000378:metabolism; D009203:Myocardial Infarction / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction; D013154:Spleen / Q000502:physiology; D020521:Stroke / Q000276:immunology / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
D015415:Biomarkers; D053583:Interleukin-1beta