Monocyte Adhesion to Xenogeneic Endothelium during Laminar Flow Is Dependent on α-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 galactoseα(1,3)galactoseβ(1,4)GlcNAc-R (α-gal) is abundantly expressed on xenogeneic endothelium. We have identified a putative receptor for α-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 α-gal, because cleavage or blockade results in a dramatic reduction in monocyte adhesion. Recruitment of human monocytes to unactivated xenogeneic endothelial cells requires both α4 and β2 integrins on the monocyte; binding of α-gal to monocytes results in rapid activation of β2, but not α4, integrins. Thus, activation of monocyte β2 integrins by α-gal expressed on xenogeneic endothelium provides a mechanism that may explain the dramatic accumulation of monocytes in vivo.