Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA–Peptide Complexes in Systemic Lupus Erythematosus

By R. Lande, D. Ganguly, V. Facchinetti, L. Frasca, C. Conrad, Josh Gregorio, S. Meller, Georgios Chamilos, Rosalie Sebasigari, V. Riccieri and 6 more. Science Translational Medicine, 2011

1,308 citations recorded by the source corpus.

In systemic lupus erythematosus, neutrophils release peptide/self-DNA complexes that trigger plasmacytoid dendritic cell activation and autoantibody formation. 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 severe and incurable autoimmune disease characterized by chronic activation of plasmacytoid dendritic cells (pDCs) and production of autoantibodies against nuclear self-antigens by hyperreactive B cells. Neutrophils are also implicated in disease pathogenesis; however, the mechanisms involved are unknown. Here, we identified in the sera of SLE patients immunogenic complexes composed of neutrophil-derived antimicrobial peptides and self-DNA. These complexes were produced by activated neutrophils in the form of web-like structures known as neutrophil extracellular traps (NETs) and efficiently triggered innate pDC activation via Toll-like receptor 9 (TLR9). SLE patients were found to develop autoantibodies to both the self-DNA and antimicrobial peptides in NETs, indicating that these complexes could also serve as autoantigens to trigger B cell activation. Circulating neutrophils from SLE patients released more NETs than those from healthy donors; this was further stimulated by the antimicrobial autoantibodies, suggesting a mechanism for the chronic release of immunogenic complexes in SLE. Our data establish a link between neutrophils, pDC activation, and autoimmunity in SLE, providing new potential targets for the treatment of this devastating disease.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/ffb6be28d58d8afe2f5dd371cd264746645c16bd

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In Immunology

1. V. Brinkmann
2. Arturo Zychlinsky
3. M. Kaplan
4. C. Lowell
5. T. Mayadas
6. X. Cullere
7. M. Radic
8. Jong-Sup Bae

Citations in the corpus

• 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).”
• Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones (2012, background): “as preeclampsia, small-vessel vasculitis and systemic lupus erythematosus [26,28,29,31,60,61].”
• A Myeloperoxidase-Containing Complex Regulates Neutrophil Elastase Release and Actin Dynamics during NETosis (2014, neutral): “…of NET degradation is linked to several diseases, including cystic fibrosis, preeclampsia, autoimmunity, and vascular diseases (Garcia-Romo et al., 2011; Hakkim et al., 2010; Kessen-brock et al., 2009; Khandpur et al., 2013; Lande et al., 2011; Papayannopoulos et al., 2011; Villanueva et al., 2011).”
• NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis (2013, background): “Because LL37 is externalized during NETosis (14, 17), it is possible that its citrullination (as well as the citrullination of other targets in the lung parenchyma) could further promote pathogenic responses in RA and other autoimmune diseases.”
• Neutrophil extracellular traps: Is immunity the second function of chromatin? (2012, background): “, 2009) and antibody–antigen complexes (Garcia­Romo et al., 2011; Lande et al., 2011), and”
• The Multifaceted Functions of Neutrophils (2013, background): “LL-37 can also potentiate functions of other immune cells, such as DCs (111).”
• Neutrophil extracellular traps (NETs): Double-edged swords of innate immunity (2012, background): “A subset of aberrant low-density granulocytes present in SLE displays enhanced capacity to form NETs and kill ECs in a NET-dependent manner.”
• Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview (2017, background): “Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3.”
• Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. (2012, background): “They have also been observed in inflammatory diseases such as preeclampsia (13), small-vessel vasculitis (14), and systemic lupus erythematosus (15).”