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

Blood. 2012 Nov 22;120(22):4421-31. doi: 10.1182/blood-2011-12-401133. Epub 2012 Sep 6.


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 FcγRIIA and glycophosphatidylinositol (GPI)-linked FcγRIIIB in IC-mediated inflammation is still debated. Here we exploited mice and cell lines expressing these human neutrophil FcγRs to demonstrate that FcγRIIIB alone, in the absence of its known signaling partners FcγRIIA and the integrin Mac-1, internalizes soluble ICs through a mechanism used by GPI-anchored receptors and fluid-phase endocytosis. FcγRIIA also uses this pathway. As shown by intravital microscopy, FcγRIIA but not FcγRIIIB-mediated neutrophil interactions with extravascular soluble ICs results in the formation of neutrophil extracellular traps (NETs) in tissues. Unexpectedly, in wild-type 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, FcγRIIIB-mediated neutrophil recruitment requires Mac-1 and is associated with the removal of intravascular IC deposits. Collectively, our studies assign a new role for FcγRIIIB in the removal of soluble ICs within the vasculature that may serve to maintain homeostasis, whereas FcγRIIA engagement of tissue soluble ICs generates NETs, a proinflammatory process linked to autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Antibody Complex / metabolism*
  • Autoimmunity / genetics
  • Endocytosis* / physiology
  • Extracellular Space / immunology
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • GPI-Linked Proteins / physiology
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Transgenic
  • Neutrophil Infiltration / genetics
  • Neutrophil Infiltration / immunology
  • Neutrophils / immunology
  • Neutrophils / metabolism*
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism
  • Receptors, IgG / physiology*
  • Solubility
  • Transfection
  • Up-Regulation / immunology
  • Up-Regulation / physiology


  • Antigen-Antibody Complex
  • FCGR3B protein, human
  • Fc gamma receptor IIA
  • GPI-Linked Proteins
  • Receptors, IgG