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

Lood, Christian LU ; Arve, Sabine LU ; Ledbetter, Jeffrey and Elkon, Keith B (2017) In Journal of Experimental Medicine 214(7). p.2103-2119
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... (More)

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.

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published
subject
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
in
Journal of Experimental Medicine
volume
214
issue
7
pages
17 pages
publisher
Rockefeller University Press
external identifiers
  • scopus:85021892248
ISSN
1540-9538
DOI
10.1084/jem.20161512
language
English
LU publication?
no
id
768327aa-bd1a-465b-9ecd-7b732be6c37a
date added to LUP
2019-03-14 09:59:48
date last changed
2019-07-16 04:05:56
@article{768327aa-bd1a-465b-9ecd-7b732be6c37a,
  abstract     = {<p>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.</p>},
  author       = {Lood, Christian and Arve, Sabine and Ledbetter, Jeffrey and Elkon, Keith B},
  issn         = {1540-9538},
  keyword      = {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},
  language     = {eng},
  month        = {06},
  number       = {7},
  pages        = {2103--2119},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Experimental Medicine},
  title        = {TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA},
  url          = {http://dx.doi.org/10.1084/jem.20161512},
  volume       = {214},
  year         = {2017},
}