TY - JOUR
T1 - Endogenous Natural Complement Inhibitor Regulates Cardiac Development
AU - Mortensen, Simon A
AU - Skov, Louise L
AU - Kjaer-Sorensen, Kasper
AU - Hansen, Annette G
AU - Hansen, Søren
AU - Dagnæs-Hansen, Frederik
AU - Jensenius, Jens C
AU - Oxvig, Claus
AU - Thiel, Steffen
AU - Degn, Søren E
N1 - Copyright © 2017 by The American Association of Immunologists, Inc.
PY - 2017/4/15
Y1 - 2017/4/15
N2 - Congenital heart defects are a major cause of perinatal mortality and morbidity, affecting >1% of all live births in the Western world, yet a large fraction of such defects have an unknown etiology. Recent studies demonstrated surprising dual roles for immune-related molecules and their effector mechanisms during fetal development and adult homeostasis. In this article, we describe the function of an endogenous complement inhibitor, mannan-binding lectin (MBL)-associated protein (MAp)44, in regulating the composition of a serine protease-pattern recognition receptor complex, MBL-associated serine protease (MASP)-3/collectin-L1/K1 hetero-oligomer, which impacts cardiac neural crest cell migration. We used knockdown and rescue strategies in zebrafish, a model allowing visualization and assessment of heart function, even in the presence of severe functional defects. Knockdown of embryonic expression of MAp44 caused impaired cardiogenesis, lowered heart rate, and decreased cardiac output. These defects were associated with aberrant neural crest cell behavior. We found that MAp44 competed with MASP-3 for pattern recognition molecule interaction, and knockdown of endogenous MAp44 expression could be rescued by overexpression of wild-type MAp44. Our observations provide evidence that immune molecules are centrally involved in the orchestration of cardiac tissue development.
AB - Congenital heart defects are a major cause of perinatal mortality and morbidity, affecting >1% of all live births in the Western world, yet a large fraction of such defects have an unknown etiology. Recent studies demonstrated surprising dual roles for immune-related molecules and their effector mechanisms during fetal development and adult homeostasis. In this article, we describe the function of an endogenous complement inhibitor, mannan-binding lectin (MBL)-associated protein (MAp)44, in regulating the composition of a serine protease-pattern recognition receptor complex, MBL-associated serine protease (MASP)-3/collectin-L1/K1 hetero-oligomer, which impacts cardiac neural crest cell migration. We used knockdown and rescue strategies in zebrafish, a model allowing visualization and assessment of heart function, even in the presence of severe functional defects. Knockdown of embryonic expression of MAp44 caused impaired cardiogenesis, lowered heart rate, and decreased cardiac output. These defects were associated with aberrant neural crest cell behavior. We found that MAp44 competed with MASP-3 for pattern recognition molecule interaction, and knockdown of endogenous MAp44 expression could be rescued by overexpression of wild-type MAp44. Our observations provide evidence that immune molecules are centrally involved in the orchestration of cardiac tissue development.
KW - Journal Article
UR - http://www.scopus.com/inward/record.url?scp=85017373237&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1601958
DO - 10.4049/jimmunol.1601958
M3 - Journal article
C2 - 28258200
SN - 0022-1767
VL - 198
SP - 3118
EP - 3126
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -