title: Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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 Center Freiburg, Freiburg, Germany (A.Z.); Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, CA (C.C.H.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Ingo
authors.initials: I
authors.lastname: Hilgendorf
authors.forename: Louisa M S
authors.initials: LM
authors.lastname: Gerhardt
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Tan
authors.forename: Carla
authors.initials: C
authors.lastname: Winter
authors.forename: Tobias A W
authors.initials: TA
authors.lastname: Holderried
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Chousterman
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Andreas
authors.initials: A
authors.lastname: Zirlik
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherer-Crosbie
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Hedrick
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000097:blood / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D009203:Myocardial Infarction / Q000097:blood* / Q000473:pathology / Q000517:prevention & control*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000097:blood / Q000502:physiology*
chemical_list: D000950:Antigens, Ly; D018836:Inflammation Mediators; C494192:Ly-6C antigen, mouse; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1
keywords: hormone receptors; macrophages; monocytes; myocardial infarction; nuclear