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

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
  • Christian Lood
  • Sabine Arve
  • Jeffrey Ledbetter
  • Keith B Elkon
External organisations
  • University of Washington, Seattle
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area

Keywords

  • Antigen-Antibody Complex/immunology, Blotting, Western, Cells, Cultured, Complement Activation/immunology, Complement C5a/immunology, Dendritic Cells/immunology, Extracellular Traps/immunology, Flow Cytometry, Humans, Lupus Erythematosus, Systemic/immunology, Monocytes/immunology, Neutrophils/immunology, Phagocytosis/immunology, Receptors, IgG/immunology, Toll-Like Receptor 7/immunology, Toll-Like Receptor 8/immunology
Original languageEnglish
Pages (from-to)2103-2119
Number of pages17
JournalJournal of Experimental Medicine
Volume214
Issue number7
Publication statusPublished - 2017 Jun 12
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes

Bibliographic note

© 2017 Lood et al.