Requirement for Vav proteins in post-recruitment neutrophil cytotoxicity in IgG but not complement C3-dependent injury.
The signals linking neutrophil opsonic receptors, FcgammaRs and complement receptor 3 (Mac-1) to cellular cytotoxic responses are poorly understood. Furthermore, because a deficiency in activating FcgammaRs reduces both IgG-mediated neutrophil recruitment and tissue injury, the role of FcgammaRs specifically in mediating neutrophil cytotoxicity in vivo remains unclear. In this study, we demonstrate that neutrophil Vav 1 and 3, guanine exchange factors for Rac GTPases, are required for IgG/FcgammaR-mediated hemorrhage and edema in the reverse passive Arthus in the lung and skin. Rac GTPases are also required for development of the reverse passive Arthus reaction. A deficiency in Vav 1 and 3 does not affect neutrophil accumulation at the site of immune complex deposition, thus uncoupling neutrophil recruitment and tissue injury. Surprisingly, Vav and Rac proteins are dispensable for the development of the local Shwartzman reaction in vivo and phagocytosis of complement-opsonized RBC in vitro, processes strictly dependent on Mac-1 and complement C3. Thus, FcgammaR signaling through the Vav and Rac proteins in neutrophils is critical for stimulating immune complex disease while Vav- and Rac-independent pathways promote Mac-1/complement C3-dependent functions.
Utomo
Ahmad
A
Department of Pathology, Center of Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Hirahashi
Junichi
J
Mekala
Divya
D
Asano
Kenichi
K
Glogauer
Michael
M
Cullere
Xavier
X
Mayadas
Tanya N
TN
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001183:Arthus Reaction / Q000235:genetics / Q000276:immunology; D003176:Complement C3 / Q000235:genetics / Q000276:immunology*; D004487:Edema / Q000235:genetics / Q000276:immunology; D006470:Hemorrhage / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D012790:Shwartzman Phenomenon / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D012867:Skin / Q000276:immunology; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000276:immunology
D000936:Antigen-Antibody Complex; D003176:Complement C3; D007074:Immunoglobulin G; D016177:Macrophage-1 Antigen; D051567:Proto-Oncogene Proteins c-vav; D017452:Receptors, IgG; D020744:rac GTP-Binding Proteins