Role of the urokinase plasminogen activator receptor in mediating impaired efferocytosis of anti-SSA/Ro-bound apoptotic cardiocytes: Implications in the pathogenesis of congenital heart block.
BACKGROUND
Binding of maternal anti-Ro/La antibodies to cognate antigen expressed on apoptotic cardiocytes decreases clearance by healthy cardiocytes, which may contribute to the development of autoimmune associated congenital heart block and fatal cardiomyopathy.


OBJECTIVE
Given recent evidence implicating the urokinase plasminogen activator receptor (uPAR) as a "don't eat me" signal during efferocytosis, experiments addressed whether surface bound anti-Ro antibodies inhibit apoptotic cell removal via an effect on the expression/function of the urokinase-type plasminogen activator protease uPA/uPAR system.


RESULTS
As assessed by flow cytometry and confocal microscopy, uPAR colocalizes and interacts with Ro60 on the surface of apoptotic human fetal cardiocytes. Blocking of uPAR enhances phagocytosis of apoptotic cardiocytes by healthy cardiocytes and reverses the anti-Ro60-dependent impaired clearance of apoptotic cardiocytes. Binding of anti-Ro60 antibodies to apoptotic cardiocytes results in increased uPAR expression, as well as enhanced uPA activity. The binding of anti-Ro60 did not alter other surface molecules involved in cell recognition (calreticulin, CD31, or CD47).


CONCLUSIONS
These data suggest that increased uPAR expression and uPA activity induced by anti-Ro60 binding to the apoptotic fetal cardiocyte provide a molecular basis by which these antibodies inhibit efferocytosis and ultimately lead to scar of the fetal conduction system and working myocardium.
Briassouli
Paraskevi
P
Department of Medicine, New York University School of Medicine, New York, 10016, USA. pbriassou@mac.com
Komissarova
Elena V
EV
Clancy
Robert M
RM
Buyon
Jill P
JP
D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis; D051928:CD47 Antigen / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D009202:Cardiomyopathies / Q000276:immunology; D002645:Chickens / Q000276:immunology; D005260:Female; D005315:Fetal Diseases / Q000235:genetics; D005333:Fetus / Q000502:physiology; D005434:Flow Cytometry; D006327:Heart Block / Q000151:congenital* / Q000209:etiology / Q000235:genetics; D006329:Heart Conduction System / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G; D051379:Mice; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000276:immunology / Q000473:pathology / Q000502:physiology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011247:Pregnancy; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors / Q000235:genetics*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; D037282:Calreticulin; D007074:Immunoglobulin G; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator