title: Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction.
abstract: BACKGROUND
  Efficient clearance of apoptotic cells (efferocytosis) is a prerequisite for inflammation resolution and tissue repair. After myocardial infarction, phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes. The molecular mechanisms of efferocytosis of cardiomyocytes and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function.
  
  
  OBJECTIVE
  We set out to identify mechanisms of dying cardiomyocyte engulfment by phagocytes and, for the first time, to assess the causal significance of disrupting efferocytosis during myocardial infarction.
  
  
  RESULTS
  In contrast to other apoptotic cell receptors, macrophage myeloid-epithelial-reproductive tyrosine kinase was necessary and sufficient for efferocytosis of cardiomyocytes ex vivo. In mice, Mertk was specifically induced in Ly6c(LO) myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic cardiomyocytes, independently of changes in noncardiomyocytes, and a reduced index of in vivo efferocytosis. Importantly, suppressed efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk; reciprocal transplantation of Mertk(+/+) marrow into Mertk(-/-) mice corrected systolic dysfunction. Interestingly, an inactivated form of myeloid-epithelial-reproductive tyrosine kinase, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of myeloid-epithelial-reproductive tyrosine kinase inactivation after myocardial infarction.
  
  
  CONCLUSIONS
  These data collectively and directly link efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.
authors.affiliation: From the Department of Pathology, Microbiology and Immunology, Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Elaine
authors.initials: E
authors.lastname: Wan
authors.forename: Xin Yi
authors.initials: XY
authors.lastname: Yeap
authors.forename: Shirley
authors.initials: S
authors.lastname: Dehn
authors.forename: Rachael
authors.initials: R
authors.lastname: Terry
authors.forename: Margaret
authors.initials: M
authors.lastname: Novak
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.forename: Shinichi
authors.initials: S
authors.lastname: Iwata
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Han
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Drosatos
authors.forename: Jon
authors.initials: J
authors.lastname: Lomasney
authors.forename: David M
authors.initials: DM
authors.lastname: Engman
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: John P
authors.initials: JP
authors.lastname: Morrow
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Edward B
authors.initials: EB
authors.lastname: Thorp
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function; D015398:Signal Transduction; D013997:Time Factors; D018183:Transplantation Chimera; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D014945:Wound Healing; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000950:Antigens, Ly; D018955:CD36 Antigens; C494192:Ly-6C antigen, mouse; D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
keywords: efferocytosis; inflammation; macrophages; myocardial infarction; phagocytosis