Monocyte adhesion to xenogeneic endothelium during laminar flow is dependent on alpha-Gal-mediated monocyte activation.
Monocytes are the predominant inflammatory cell recruited to xenografts and participate in delayed xenograft rejection. In contrast to allogeneic leukocytes that require up-regulation of endothelial adhesion molecules to adhere and emigrate into effector tissues, we demonstrate that human monocytes adhere rapidly to unstimulated xenogeneic endothelial cells. The major xenoantigen galactosealpha(1,3)galactosebeta(1,4)GlcNAc-R (alpha-gal) is abundantly expressed on xenogeneic endothelium. We have identified a putative receptor for alpha-gal on human monocytes that is a member of the C-type family of lectin receptors. Monocyte arrest under physiological flow conditions is regulated by alpha-gal, because cleavage or blockade results in a dramatic reduction in monocyte adhesion. Recruitment of human monocytes to unactivated xenogeneic endothelial cells requires both alpha(4) and beta(2) integrins on the monocyte; binding of alpha-gal to monocytes results in rapid activation of beta(2), but not alpha(4), integrins. Thus, activation of monocyte beta(2) integrins by alpha-gal expressed on xenogeneic endothelium provides a mechanism that may explain the dramatic accumulation of monocytes in vivo.
Peterson
Mark D
MD
Division of Cardiac Surgery, Department of Surgery, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Jin
Rongyu
R
Hyduk
Sharon
S
Duchesneau
Pascal
P
Cybulsky
Myron I
MI
Waddell
Thomas K
TK
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015478:Antigens, Heterophile / Q000378:metabolism / Q000502:physiology*; D018821:CD18 Antigens / Q000502:physiology; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D004187:Disaccharides / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D039441:Integrin alpha4 / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020014:K562 Cells; D019041:L-Selectin / Q000502:physiology; D037181:Lectins, C-Type / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D009000:Monocytes / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000276:immunology; D012212:Rheology / Q000379:methods; D013552:Swine; D014312:Trisaccharides / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015703:Antigens, CD; D015478:Antigens, Heterophile; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D004187:Disaccharides; D000939:Epitopes; C065289:ICAM2 protein, human; D037181:Lectins, C-Type; D008024:Ligands; D014312:Trisaccharides; D019010:Vascular Cell Adhesion Molecule-1; C076569:alpha-galactosyl epitope; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; C055075:galactosyl-(1-3)galactose; D039441:Integrin alpha4