title: Cardiomyocytes induce macrophage receptor shedding to suppress phagocytosis.
abstract: BACKGROUND
  Mobilization of the innate immune response to clear and metabolize necrotic and apoptotic cardiomyocytes is a prerequisite to heart repair after cardiac injury. Suboptimal kinetics of dying myocyte clearance leads to secondary necrosis, and in the case of the heart, increased potential for collateral loss of neighboring non-regenerative myocytes. Despite the importance of myocyte phagocytic clearance during heart repair, surprisingly little is known about its underlying cell and molecular biology.
  
  
  OBJECTIVE
  To determine if phagocytic receptor MERTK is expressed in human hearts and to elucidate key sequential steps and phagocytosis efficiency of dying adult cardiomyocytes, by macrophages.
  
  
  RESULTS
  In infarcted human hearts, expression profiles of the phagocytic receptor MER-tyrosine kinase (MERTK) mimicked that found in experimental ischemic mouse hearts. Electron micrographs of myocardium identified MERTK signal along macrophage phagocytic cups and Mertk-/- macrophages contained reduced digested myocyte debris after myocardial infarction. Ex vivo co-culture of primary macrophages and adult cardiomyocyte apoptotic bodies revealed reduced engulfment relative to resident cardiac fibroblasts. Inefficient clearance was not due to the larger size of myocyte apoptotic bodies, nor were other key steps preceding the formation of phagocytic synapses significantly affected; this included macrophage chemotaxis and direct binding of phagocytes to myocytes. Instead, suppressed phagocytosis was directly associated with myocyte-induced inactivation of MERTK, which was partially rescued by genetic deletion of a MERTK proteolytic susceptibility site.
  
  
  CONCLUSIONS
  Utilizing an ex vivo co-cultivation approach to model key cellular and molecular events found in vivo during infarction, cardiomyocyte phagocytosis was found to be inefficient, in part due to myocyte-induced shedding of macrophage MERTK. These findings warrant future studies to identify other cofactors of macrophage-cardiomyocyte cross-talk that contribute to cardiac pathophysiology.
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA.
authors: Shuang
authors: S
authors: Zhang
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA.
authors: Xin-Yi
authors: XY
authors: Yeap
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA.
authors: Lubov
authors: L
authors: Grigoryeva
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA.
authors: Shirley
authors: S
authors: Dehn
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA.
authors: Matthew
authors: M
authors: DeBerge
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA.
authors: Michael
authors: M
authors: Tye
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA.
authors: Emily
authors: E
authors: Rostlund
authors: University of Antwerp, Belgium.
authors: Dorien
authors: D
authors: Schrijvers
authors: University of Antwerp, Belgium.
authors: Zheng Jenny
authors: ZJ
authors: Zhang
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA.
authors: Ronen
authors: R
authors: Sumagin
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA.
authors: Warren G
authors: WG
authors: Tourtellotte
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA.
authors: Daniel
authors: D
authors: Lee
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA.
authors: Jon
authors: J
authors: Lomasney
authors: Department of Cardiology and Division of Molecular Medicine, Columbia University, New York, NY, USA.
authors: John
authors: J
authors: Morrow
authors: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA. Electronic address: ebthorp@northwestern.edu.
authors: Edward B
authors: EB
authors: Thorp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D018920:Coculture Techniques; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009203:Myocardial Infarction / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics* / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D000076202:c-Mer Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
keywords: Acute myocardial infarction; Animal models of human disease; Cardiomyocyte; Phagocytosis