Complement alternative pathway acts as a positive feedback amplification of neutrophil activation.
Complement alternative pathway plays an important, but not clearly understood, role in neutrophil-mediated diseases. We here show that neutrophils themselves activate complement when stimulated by cytokines or coagulation-derived factors. In whole blood, tumor necrosis factor/formyl-methionyl-leucyl-phenylalanine or phorbol myristate acetate resulted in C3 fragments binding on neutrophils and monocytes, but not on T cells. Neutrophils, stimulated by tumor necrosis factor, triggered the alternative pathway on their surface in normal and C2-depleted, but not in factor B-depleted serum and on incubation with purified C3, factors B and D. This occurred independently of neutrophil proteases, oxidants, or apoptosis. Neutrophil-secreted properdin was detected on the cell surface and could focus "in situ" the alternative pathway activation. Importantly, complement, in turn, led to further activation of neutrophils, with enhanced CD11b expression and oxidative burst. Complement-induced neutrophil activation involved mostly C5a and possibly C5b-9 complexes, detected on tumor necrosis factor- and serum-activated neutrophils. In conclusion, neutrophil stimulation by cytokines results in an unusual activation of autologous complement by healthy cells. This triggers a new amplification loop in physiologic innate immunity: Neutrophils activate the alternative complement pathway and release C5 fragments, which further amplify neutrophil proinflammatory responses. This mechanism, possibly required for effective host defense, may be relevant to complement involvement in neutrophil-mediated diseases.
INSERM U845, Université René Descartes, Hôpital Necker, 161 rue de Sèvres, Paris, France.
Laurent
L
Camous
Lubka
L
Roumenina
Sylvain
S
Bigot
Soumeya
S
Brachemi
Véronique
V
Frémeaux-Bacchi
Philippe
P
Lesavre
Lise
L
Halbwachs-Mecarelli
D001769:Blood / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects / Q000502:physiology; D003176:Complement C3 / Q000378:metabolism; D003182:Complement C5 / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000187:drug effects / Q000502:physiology*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D003176:Complement C3; D003182:Complement C5; D014409:Tumor Necrosis Factor-alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine; C042205:methionyl-leucyl-phenylalanine; D013755:Tetradecanoylphorbol Acetate