TY - JOUR
T1 - Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis
AU - Leuschner, Florian
AU - Rauch, Philipp J.
AU - Ueno, Takuya
AU - Gorbatov, Rostic
AU - Marinelli, Brett
AU - Lee, Won Woo
AU - Dutta, Partha
AU - Wei, Ying
AU - Robbins, Clinton
AU - Iwamoto, Yoshiko
AU - Sena, Brena
AU - Chudnovskiy, Aleksey
AU - Panizzi, Peter
AU - Keliher, Edmund
AU - Higgins, John M.
AU - Libby, Peter
AU - Moskowitz, Michael A.
AU - Pittet, Mikael J.
AU - Swirski, Filip K.
AU - Weissleder, Ralph
AU - Nahrendorf, Matthias
PY - 2012/1
Y1 - 2012/1
N2 - 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/M 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.
AB - 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/M 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.
UR - http://www.scopus.com/inward/record.url?scp=84863115989&partnerID=8YFLogxK
U2 - 10.1084/jem.20111009
DO - 10.1084/jem.20111009
M3 - Article
C2 - 22213805
AN - SCOPUS:84863115989
SN - 0022-1007
VL - 209
SP - 123
EP - 137
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -