Endothelial endoglin is involved in inflammation: role in leukocyte adhesion and transmigration.
Human endoglin is an RGD-containing transmembrane glycoprotein identified in vascular endothelial cells. Although endoglin is essential for angiogenesis and its expression is up-regulated in inflammation and at sites of leukocyte extravasation, its role in leukocyte trafficking is unknown. This function was tested in endoglin heterozygous mice (Eng(+/-)) and their wild-type siblings Eng(+/+) treated with carrageenan or LPS as inflammatory agents. Both stimuli showed that inflammation-induced leukocyte transendothelial migration to peritoneum or lungs was significantly lower in Eng(+/-) than in Eng(+/+) mice. Leukocyte transmigration through cell monolayers of endoglin transfectants was clearly enhanced in the presence of endoglin. Coating transwells with the RGD-containing extracellular domain of endoglin, enhanced leukocyte transmigration, and this increased motility was inhibited by soluble endoglin. Leukocytes stimulated with CXCL12, a chemokine involved in inflammation, strongly adhered to endoglin-coated plates and to endoglin-expressing endothelial cells. This endoglin-dependent adhesion was abolished by soluble endoglin, RGD peptides, the anti-integrin α5β1 inhibitory antibody LIA1/2 and the chemokine receptor inhibitor AMD3100. These results demonstrate for the first time that endothelial endoglin interacts with leukocyte integrin α5β1 via its RGD motif, and this adhesion process is stimulated by the inflammatory chemokine CXCL12, suggesting a regulatory role for endoglin in transendothelial leukocyte trafficking.
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
Elisa
E
Rossi
Francisco
F
Sanz-Rodriguez
Nelida
N
Eleno
Annette
A
Düwell
Francisco J
FJ
Blanco
Carmen
C
Langa
Luisa M
LM
Botella
Carlos
C
Cabañas
José M
JM
Lopez-Novoa
Carmelo
C
Bernabeu
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D054441:Cell Migration Assays, Leukocyte; D054377:Chemokine CXCL12 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D011956:Receptors, Cell Surface / Q000378:metabolism*; D057688:Transcellular Cell Migration / Q000502:physiology; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*
D015703:Antigens, CD; D054377:Chemokine CXCL12; C064206:ENG protein, human; D000071063:Endoglin; D039081:Integrin alpha5beta1; D011956:Receptors, Cell Surface