TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA

J Exp Med. 2017 Jul 3;214(7):2103-2119. doi: 10.1084/jem.20161512. Epub 2017 Jun 12.


Neutrophils play a crucial role in host defense. However, neutrophil activation is also linked to autoimmune diseases such as systemic lupus erythematosus (SLE), where nucleic acid-containing immune complexes (IC) drive inflammation. The role of Toll-like receptor (TLR) signaling in processing of SLE ICs and downstream inflammatory neutrophil effector functions is not known. We observed that TLR7/8 activation leads to a furin-dependent proteolytic cleavage of the N-terminal part of FcgRIIA, shifting neutrophils away from phagocytosis of ICs toward the programmed form of necrosis, NETosis. TLR7/8-activated neutrophils promoted cleavage of FcgRIIA on plasmacytoid dendritic cells and monocytes, resulting in impaired overall clearance of ICs and increased complement C5a generation. Importantly, ex vivo derived activated neutrophils from SLE patients demonstrated a similar cleavage of FcgRIIA that was correlated with markers of disease activity, as well as complement activation. Therapeutic approaches aimed at blocking TLR7/8 activation would be predicted to increase phagocytosis of circulating ICs, while disarming their inflammatory potential.

MeSH terms

  • Antigen-Antibody Complex / immunology*
  • Blotting, Western
  • Cells, Cultured
  • Complement Activation / immunology
  • Complement C5a / immunology
  • Complement C5a / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Extracellular Traps / immunology
  • Extracellular Traps / metabolism
  • Flow Cytometry
  • Humans
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / metabolism
  • Monocytes / immunology
  • Monocytes / metabolism
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Phagocytosis / immunology*
  • Receptors, IgG / immunology*
  • Receptors, IgG / metabolism
  • Toll-Like Receptor 7 / immunology*
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 8 / immunology*
  • Toll-Like Receptor 8 / metabolism


  • Antigen-Antibody Complex
  • FCGR2A protein, human
  • Receptors, IgG
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Complement C5a