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Ly-6C high Monocytes Depend on Nr4a1 to Balance Both Inflammatory and Reparative Phases in the Infarcted Myocardium

Hilgendorf, Ingo, Gerhardt, Louisa M.S., Tan, Timothy C., Winter, Carla, Holderried, Tobias A.W., Chousterman, Benjamin G., Iwamoto, Yoshiko, Liao, Ronglih, Zirlik, Andreas, Scherer-Crosbie, Marielle, Hedrick, Catherine C., Libby, Peter, Nahrendorf, Matthias, Weissleder, Ralph, Swirski, Filip K.·2014·Circulation Research
DOI 10.1161/circresaha.114.303204PMC PMC4017349
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Abstract

Rationale: Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6C) high and reparative Ly-6C low 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-6C low monocyte production but dispensable to Ly-6C low 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-6C high monocytes infiltrate the infarcted myocardium and, unlike Ly-6C low monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6C high monocytes accrue in response to a brief C–C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6C high monocytes give rise to reparative Ly-6C low F4/80 high 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-6C high monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.

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Metadata

Authors
Hilgendorf, I., Gerhardt, L. M. S., Tan, T. C., Winter, C., Holderried, T. A. W., Chousterman, B. G., Iwamoto, Y., Liao, R., Zirlik, A., Scherer-Crosbie, M., Hedrick, C. C., Libby, P., Nahrendorf, M., Weissleder, R., & Swirski, F. K.
Affiliations
From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women’s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart...
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2014-05-09
Volume
114
Issue
10
Pages
1611-1622
ISSN
  • 0009-7330
  • 1524-4571
DOI
10.1161/circresaha.114.303204
PMC
PMC4017349
Cited by
559
References
9
Language
en

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CoChat. (2026). Citation check: Ly-6C high Monocytes Depend on Nr4a1 to Balance Both Inflammatory and Reparative Phases in the Infarcted Myocardium. https://app.cochat.ai/papers/10.1161/circresaha.114.303204
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Hilgendorf, I., Gerhardt, L. M. S., Tan, T. C., Winter, C., Holderried, T. A. W., Chousterman, B. G., Iwamoto, Y., Liao, R., Zirlik, A., Scherer-Crosbie, M., Hedrick, C. C., Libby, P., Nahrendorf, M., Weissleder, R., & Swirski, F. K. (2014). Ly-6C high Monocytes Depend on Nr4a1 to Balance Both Inflammatory and Reparative Phases in the Infarcted Myocardium. Circulation Research. https://doi.org/10.1161/circresaha.114.303204