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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Christian Lood
  • Sabine Arve
  • Jeffrey Ledbetter
  • Keith B Elkon
Externa organisationer
  • University of Washington, Seattle
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Immunologi inom det medicinska området

Nyckelord

Originalspråkengelska
Sidor (från-till)2103-2119
Antal sidor17
TidskriftJournal of Experimental Medicine
Volym214
Utgivningsnummer7
StatusPublished - 2017 jun 12
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa