The lectin-like domain of complement receptor 3 protects endothelial barrier function from activated neutrophils.
The adhesion of neutrophils to endothelial cells is a central event leading to diapedesis and involves the binding of the I-domain of beta(2) integrins (CD11/CD18) to endothelial ICAMs. In addition to the I-domain, the beta(2) integrin complement receptor 3 (CR3) (CD11b/CD18) contains a lectin-like domain (LLD) that can alter leukocyte functions such as chemotaxis and cytotoxicity. The present study demonstrates that, in contrast to the CR3 I-domain, Ab blockade of the CR3 LLD has no role in mediating neutrophil-induced loss of endothelial barrier function. However, activation of CR3 with the LLD agonist beta-glucan protects the barrier function of endothelial cells in the presence of activated neutrophils and reduces transendothelial migration without affecting adhesion of the neutrophils to the endothelium. The LLD site-specific mAb VIM12 obviates beta-glucan protection while activation of the LLD by VIM12 cross-linking mimics the beta-glucan response by both preserving endothelial barrier function and reducing neutrophil transendothelial migration. beta-glucan has no direct effect on endothelial cell function in the absence of activated neutrophils. These findings demonstrate that signaling through the CR3 LLD prevents neutrophil-induced loss of endothelial barrier function and reduces diapedesis. This suggests that the LLD may be a suitable target for oligosaccharide-based anti-inflammatory therapeutics.
Tsikitis
Vassiliki L
VL
Department of Surgery, Rhode Island Hospital and Brown University Medical School, Providence, RI 02903, USA.
Morin
Nicole A
NA
Harrington
Elizabeth O
EO
Albina
Jorge E
JE
Reichner
Jonathan S
JS
D002634:Chemotaxis, Leukocyte; D042783:Endothelial Cells / Q000502:physiology*; D005936:Glucans / Q000502:physiology; D006801:Humans; D037102:Lectins; D016177:Macrophage-1 Antigen / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D018375:Neutrophil Activation; D009504:Neutrophils / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D005936:Glucans; D037102:Lectins; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha