Activation of Rac2 and Cdc42 on Fc and complement receptor ligation in human neutrophils

Abstract: Phagocytosis is a complex process en-gaging a concerted action of signal-transduction cascades that leads to ingestion, subsequent phagoly-sosome fusion, and oxidative activation. We have previously shown that in human neutrophils, C3bi-mediated phagocytosis elicits a significant oxidative response, suggesting that activation of the small GTPase Rac is involved in this process. This is contradictory to macrophages, where only Fc re-ceptor for immunoglobulin G (FcR)-mediated ac-tivation is Rac-dependent. The present study shows that engagement of the complement receptor 3 (CR3) and FcR and CR3- and FcR-mediated phagocytosis activates Rac, as well as Cdc42. Fur-thermore, following receptor-engagement of the CR3 or FcRs, a downstream target of these small GTPases, p21-activated kinase, becomes phos-phorylated, and Rac2 is translocated to the mem-brane fraction. Using the methyltransferase inhib-itors N-acetyl-S-farnesyl-L-cysteine and N-acetyl-S-geranylgeranyl-L-cysteine, we found that the phagocytic uptake of bacteria was not Rac2- or Cdc42-dependent, whereas the oxidative activa-tion was decreased. In conclusion, our results in-dicate that in neutrophils, Rac2 and Cdc42 are involved in FcR- and CR3-induced activation and for properly functioning signal transduction in-volved in the generation of oxygen radicals. J