Endocytosis of soluble immune complexes leads to their clearance by FcγRIIIB but induces neutrophil extracellular traps via FcγRIIA in vivo

Soluble immune complexes (ICs) are abundant in autoimmune diseases, yet neutrophil responses to these soluble humoral factors remain uncharacterized. Moreover, the individual role of the uniquely human Fc gamma RIIA and glycophos-phatidylinositol (GPI)-linked Fc gamma RIIIB in IC-mediated inflammation is still debated. Here we exploited mice and cell lines expressing these human neutrophil Fc gamma Rs to demonstrate that Fc gamma RIIIB alone, in the absence of its known signaling partners Fc gamma RIIA and the integrin Mac-1, internalizes soluble ICs through a mechanism used by GPI-anchored receptors and fluid-phase endocytosis. Fc gamma RIIA also uses this pathway. As shown by intravital microscopy, Fc gamma RIIA but not Fc gamma RIIIB-mediated neutrophil interactions with extravascular soluble ICs results in the formation of neutrophil extracellular traps (NETs) in tissues. Unexpectedly, in wildtype mice, IC-induced NETosis does not rely on the NADPH oxidase, myeloperoxidase, or neutrophil elastase. In the context of soluble ICs present primarily within vessels, Fc gamma RIIIB-mediated neutrophil recruitment requires Mac-1 and is associated with the removal of intravascular IC deposits. Collectively, our studies assign a new role for Fc gamma RIIIB in the removal of soluble ICs within the vasculature that may serve to maintain homeostasis, whereas Fc gamma RIIA engagement of tissue soluble ICs generates NETs, a proinflammatory process linked to autoimmunity. (Blood. 2012;120(22):4421-4431)