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

By G. García-Romo, S. Caielli, B. Vega, J. Connolly, F. Allantaz, Zhaohui Xu, M. Punaro, Jeanine Baisch, C. Guiducci, R. Coffman and 3 more. Science Translational Medicine, 2011

1,373 citations recorded by the source corpus.

In systemic lupus erythematosus, neutrophil extracellular traps activate plasmacytoid dendritic cells to produce type I interferon. Lupus Neutrophils Cast a Wide NET Systemic lupus erythematosus, also known as SLE or lupus, is a systemic, chronic autoimmune disease that can affect the skin, joints, kidneys, and other organs. In lupus, the body’s immune system turns against antigens in the body’s own nuclei, with activated B cells producing antibodies against self-DNA and associated proteins. The resulting immune complexes accumulate in the body, causing inflammation and tissue damage. Now, two new studies, by Lande et al. and Garcia-Romo et al., demonstrate a role for neutrophils and the “neutrophil extracellular traps,” a specialized structure they release when activated, in the pathogenesis of the disease. A key characteristic of lupus is the presence of chronically activated plasmacytoid dendritic cells, which secrete type I interferons. Lupus patients also display increased numbers of immature neutrophils in the blood, but the exact role of neutrophils in the disease had been unclear. Lande et al. began with the observation that patient serum contains immunogenic complexes that include the antimicrobial peptide LL37, human neutrophil peptide (HNP), and self-DNA. These complexes are taken up by and activate dendritic cells, and patients carry antibodies directed against LL37, HNP, and self-DNA. What is the origin of these complexes? Activated neutrophils can undergo NETosis, a particular type of cell death in which their nuclear DNA is released in long chromatin filaments that form web-like structures, neutrophil extracellular traps (NETs). NETs contain antimicrobial peptides, and can entrap bacteria, enabling them to be killed. Lande et al. now show that the anti-LL37 and anti-HNP antibodies present in lupus patient serum can activate neutrophils and induce them to release NETs. Patient-derived neutrophils release more NETs upon exposure to antibody than control neutrophils. In a parallel study, Garcia-Romo et al. look in detail at neutrophils in lupus, and show that lupus patient neutrophils undergo accelerated cell death in culture. Anti-ribonucleoprotein antibodies present in patient serum induce NETosis, and the released NETs contain LL37 and another neutrophil protein, HMGB1. Induction of NETosis requires FcRIIa, signaling through the pattern recognition receptor Toll-like receptor 7, and formation of reactive oxygen species. Garcia-Romo et al. also show that these NETs potently activate dendritic cells, leading to secretion of high levels of interferon-α. Together, these findings portray an important role for neutrophils in lupus pathogenesis, whereby neutrophils activated by anti-self antibodies release NETs. These NETs, which contain antimicrobial peptides complexed with self-DNA, activate plasmacytoid dendritic cells, leading to interferon release and furtherment and aggravation of inflammation and disease. 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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/aa46fa67bcdbca913f840d6749107dd3a9e099d7

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In Immunology

1. A. Mócsai
2. C. Rosales
3. D. Wagner
4. M. Kaplan
5. Jong-Sup Bae
6. Steffen Massberg
7. C. Lowell
8. V. Brinkmann

Citations in the corpus

• Personalized Immunomonitoring Uncovers Molecular Networks That Stratify Lupus Patients (2016, neutral): “In lupus, these cells are primed by IFN and release both pro-inflammatory mediators and interferogenic DNA when exposed to SLE ICs (Garcia-Romo et al., 2011; Hakkim et al., 2010; Villanueva et al., 2011).”
• Neutrophil extracellular traps (NETs): Double-edged swords of innate immunity (2012, background): “been implicated in the induction of NETs (2, 24, 57).”
• Netting neutrophils induce endothelial damage, infiltrate tissues and expose immunostimulatory molecules in systemic lupus erythematosus (2011, background): “While this manuscript was in the process of being accepted, two articles that also demonstrate the putative importance of NETs in lupus have been published (65, 66).”
• Diverse novel functions of neutrophils in immunity, inflammation, and beyond (2013, background): “Two recent studies on human patients shed novel light on the role of pDCs, type I interferons, and neutrophils in the core pathogenesis of SLE (Lande et al., 2011; Garcia-Romo et al., 2011; Fig.”
• Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview (2017, background): “It has been observed that, in SLE patients, IFN-α is a potent NETosis inducer (139) and, along with activated pDC-derived IL-6, promotes the differentiation of autoantibody-secreting autoreactive B cells (140).”
• Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo (2012, background): “Interestingly, generation of NETs has recently been reported in disease states known to be linked with an increased risk of thrombotic disorders, such as systemic lupus erythematosus (Garcia-Romo et al., 2011).”
• Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? (2018, background): “…patients were also reported to readily form NETs (Villanueva et al., 2011), and because these NETs presented autoantigens, it has been suggested that LDNs in these patients are responsible for sustaining chronic inflammation leading to autoimmunity (Garcia-Romo et al., 2011; Khandpur et al., 2013).”
• Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment (2016, background): “M2-like macrophages express high levels of macrophage mannose receptor (MMR) and IL-10 and low levels of HLADR and IL-1𝛽 [66].”