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

作者：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-Cro**ie, Marielle; Hedrick, Catherine C.; Libby, Peter; Nahrendorf, Matthias; Weissleder, Ralph; Swirski, Filip K.^*

来源：Circulation Research, 2014, 114(10): 1611-1622.

DOI：10.1161/CIRCRESAHA.114.303204

• hormone receptors
• nuclear
• macrophages
• monocytes
• myocardial infarction

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/M). According to 1 model, Mo/M 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/M phi 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.

• 出版日期2014-5-9