Immune complex stimulation of neutrophil apoptosis: Investigating the involvement of oxidative and nonoxidative pathways

Neutrophils are involved in the pathogenesis of various inflammatory diseas es. One of the mechanisms by which neutrophilic inflammation is generated i s immune complex (IC) deposition in tissue. As the clearance of apoptotic n eutrophils from inflamed sites is considered a crucial determinant for the resolution of inflammation, we investigated the effects of IC-induced neutr ophil activation on apoptosis and the mechanisms regulating neutrophil surv ival. Our results show that IC stimulated apoptosis efficiently. The percen tage of apoptotic neutrophils was reduced by the anti-Fc gamma RII mAb IV.3 , but not by anti-Fc gamma RIII mAb 3G8. The spontaneous apoptosis was comp letely inhibited by the antioxidant compound catalase, which in turn preven ted only partially the apoptosis in presence of IC. The oxidative metabolis m triggered by IC was inhibited only blocking both Fc gamma RII and Fc gamm a RIII. Neutrophils from patients with chronic granulomatous disease, conge nitally incapable of producing oxidants, showed low level of spontaneous ap optosis, but underwent a nearly 3-fold increment in the apoptosis rate when incubated with IC. In conclusion, neutrophil apoptosis appears to be a pro cess governed by multiple pathways, some of which are strictly ROS-dependen t, others acting in a nonoxidative manner. In particular, the herein shown Fc gamma RII-dependent, ROS-independent, signal-inducing neutrophil apoptos is may uncover new pharmacological targets for the promotion of cell remova l from sites of inflammation, thereby favoring the resolution of the inflam matory process. (C) 2001 Elsevier Science Inc.