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The Lectin-Like Domain of Complement Receptor 3 Protects Endothelial Barrier Function from Activated Neutrophils¹

Vassiliki L. Tsikitis^*, Nicole A. Morin, Elizabeth O. Harrington, Jorge E. Albina^* and Jonathan S. Reichner^2,*

^* Department of Surgery, Rhode Island Hospital and Brown University Medical School, Providence, RI 02903; and Pulmonary Vascular Biology Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Brown University Medical School, Providence, RI 02912

The adhesion of neutrophils to endothelial cells is a central event leading to diapedesis and involves the binding of the I-domain of ₂ integrins (CD11/CD18) to endothelial ICAMs. In addition to the I-domain, the 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 -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 -glucan protection while activation of the LLD by VIM12 cross-linking mimics the -glucan response by both preserving endothelial barrier function and reducing neutrophil transendothelial migration. -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.

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