title: The lectin-like domain of complement receptor 3 protects endothelial barrier function from activated neutrophils.
abstract: 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.
authors.affiliation: Department of Surgery, Rhode Island Hospital and Brown University Medical School, Providence, RI 02903, USA.
authors.forename: Vassiliki L
authors.initials: VL
authors.lastname: Tsikitis
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Morin
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Harrington
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Albina
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Reichner
mesh_terms: 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
chemical_list: D005936:Glucans; D037102:Lectins; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha