Role of TNF priming and adhesion molecules in neutrophil recruitment to intravascular immune complexes.
Neutrophils play an important role in immune complex (IC)-mediated diseases, but the mechanisms underlying their recruitment to sites of IC deposition remain largely undefined. Furthermore, neutrophils encounter cytokines that prime their effector functions, yet the physiological relevance of priming to neutrophil functions is unclear. Using intravital microscopy, we demonstrate that TNF treatment of neutrophils ex vivo significantly increased their adhesion in a model of intravascular ICs deposited in the cremaster muscle. Notably, TNF priming had no effect on neutrophil adhesion in the absence of ICs. Analyses of relevant knockout mice and neutrophil reconstitution revealed a critical role for FcgammaRs and the CD18 integrin Mac-1 in IC-mediated neutrophil adhesion. Furthermore, ICAM-1, a major Mac-1 ligand constitutively expressed on unactivated endothelium, significantly contributed to this process. These data suggest that TNF priming promotes FcgammaR interaction with intravascular ICs, leading to the binding of Mac-1 to ICAM-1 and subsequent neutrophil arrest.
Lauterbach
Michael
M
Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
O'Donnell
Peter
P
Asano
Kenichi
K
Mayadas
Tanya N
TN
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002448:Cell Adhesion; D007105:Immune Complex Diseases / Q000209:etiology*; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D017452:Receptors, IgG / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016177:Macrophage-1 Antigen; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1