Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)–induced and neutrophil-related transcripts. Increased production and/or bioavailability of IFN-α and associated alterations in dendritic cell (DC) homeostasis have been linked to lupus pathogenesis. Although neutrophils have long been shown to be associated with lupus, their potential role in disease pathogenesis remains elusive. Here, we show that mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophil extracellular traps (NETs). SLE NETs contain DNA as well as large amounts of LL37 and HMGB1, neutrophil proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid DCs (pDCs). Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and TLR9 (Toll-like receptor 9)–dependent manner. Our results reveal an unsuspected role for neutrophils in SLE pathogenesis and identify a novel link between nucleic acid–recognizing antibodies and type I IFN production in this disease.

Changing world of neutrophils

“…They were shown to activate dendritic cells via TLR9 receptors [38,61], linking thereby innate and adaptive immune processes. Activation of platelets via TLR2 and TLR4 receptors [101] and degradation of coagulation inhibitory proteins by proteases on the surface of NETs both promote blood clotting which also impairs bacterial dissemination [51,69].…”

Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients

“…The activation of DCs by NETs appears to play an important role in the pathogenesis of some autoimmune diseases such as psoriasis (Lande et al, 2007), systemic lupus erythematosus (SLE) (Barrat et al, 2005;Garcia-Romo et al, 2011;Lande et al, 2011;Means et al, 2005) small vessel vasculitis (Sangaletti et al, 2012) and type I diabetes (Diana et al, 2013). NETsactivated pDCs produce large amounts of interferon that can lead to the maturation of myeloid DCs (mDCs) and exert an effect on T cell function.…”

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

“…PDC can also be activated by neutrophil extracellular traps (NET), released by dying or activated neutrophils. These NET contain DNA fibers, histones, as well as a large amount of LL37 and HMGB1 52, 53 . Human PDC can also be activated by CD154 from activated platelets 54 or endothelial-derived microvesicles 6, 46 .…”

“…Moreover, high levels of type I IFN released by PDC may be detrimental in chronic inflammatory or autoimmune diseases 7, 54, 68– 71 . This is the case of systemic lupus erythematosus (SLE) 52– 54 , type 1 diabetes 69 , and psoriasis 41, 71 . Furthermore, PDC may participate in inflammatory autoimmune disorders ( i.e ., systemic sclerosis 70 or autoimmune vasculitis 72 ) via the secretion of other pro-inflammatory cytokines than type I IFN 72 or chimiokines 70 .…”