TY - JOUR
T1 - Ly-6 chigh monocytes depend on nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium
AU - Hilgendorf, Ingo
AU - Gerhardt, Louisa M.S.
AU - Tan, Timothy C.
AU - Winter, Carla
AU - Holderried, Tobias A.W.
AU - Chousterman, Benjamin G.
AU - Iwamoto, Yoshiko
AU - Liao, Ronglih
AU - Zirlik, Andreas
AU - Scherer-Crosbie, Marielle
AU - Hedrick, Catherine C.
AU - Libby, Peter
AU - Nahrendorf, Matthias
AU - Weissleder, Ralph
AU - Swirski, Filip K.
PY - 2014
Y1 - 2014
N2 - RATIONALE:: Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6Chigh) and reparative Ly-6Clow monocytes/macrophages (Mo/MΦ). According to 1 model, Mo/MΦ heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from 1 circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1), is essential to Ly-6Clow monocyte production but dispensable to Ly-6Clow macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity. OBJECTIVE:: This study tested the role of Nr4a1 in myocardial infarction in the context of the 2 Mo/MΦ accumulation scenarios. METHODS AND RESULTS:: We show that Ly-6Chigh monocytes infiltrate the infarcted myocardium and, unlike Ly-6Chigh monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6Chigh monocytes accrue in response to a brief C-C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6Chigh monocytes give rise to reparative Ly-6Chigh F4/80 macrophages that proliferate locally. In the absence of Nr4a1, Ly-6C high monocytes express heightened levels of C-C chemokine receptor 2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function. CONCLUSIONS:: Ly-6Chigh monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.
AB - RATIONALE:: Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6Chigh) and reparative Ly-6Clow monocytes/macrophages (Mo/MΦ). According to 1 model, Mo/MΦ heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from 1 circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1), is essential to Ly-6Clow monocyte production but dispensable to Ly-6Clow macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity. OBJECTIVE:: This study tested the role of Nr4a1 in myocardial infarction in the context of the 2 Mo/MΦ accumulation scenarios. METHODS AND RESULTS:: We show that Ly-6Chigh monocytes infiltrate the infarcted myocardium and, unlike Ly-6Chigh monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6Chigh monocytes accrue in response to a brief C-C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6Chigh monocytes give rise to reparative Ly-6Chigh F4/80 macrophages that proliferate locally. In the absence of Nr4a1, Ly-6C high monocytes express heightened levels of C-C chemokine receptor 2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function. CONCLUSIONS:: Ly-6Chigh monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.
KW - Hormone receptors, nuclear
KW - Macrophages
KW - Monocytes
KW - myocardial infarction
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U2 - 10.1161/CIRCRESAHA.114.303204
DO - 10.1161/CIRCRESAHA.114.303204
M3 - Article
C2 - 24625784
AN - SCOPUS:84901056045
SN - 0009-7330
VL - 114
SP - 1611
EP - 1622
JO - Circulation research
JF - Circulation research
IS - 10
ER -