Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus

Pieterse, Elmar; Hofstra, Julia M.; Berden, Jo H. M.; Herrmann, Martin; Dieker, Jürgen; Vlag, Johan van der

doi:10.1111/cei.12359

Cited by 98 publications

(82 citation statements)

References 26 publications

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“…Notably, in contrast to our experience in murine LN kidneys, a reliable staining of human LN biopsies for citrullinated histone H3 could not be obtained (data not shown). Stainings with monoclonal antibodies KM-2 (against triacetylated histone H4 [K8, 12,16] Notably, these histone modifications were previously shown to be enriched in NETs when compared with unstimulated neutrophils. 12 Taken all stainings together, the glomerular presence of NETs could be identified in 7 of the 8 renal biopsies, ranging from 18% to 75% NET-positive glomeruli.…”

Section: Glomerular Nets Are Associated With Proteinuria and Endmt Inmentioning

confidence: 99%

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Pieterse

Rother

Garsen

et al. 2017

ATVB

199

150

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Objective— An excessive release and impaired degradation of neutrophil extracellular traps (NETs) leads to the continuous exposure of NETs to the endothelium in a variety of hematologic and autoimmune disorders, including lupus nephritis. This study aims to unravel the mechanisms through which NETs jeopardize vascular integrity. Approach and Results— Microvascular and macrovascular endothelial cells were exposed to NETs, and subsequent effects on endothelial integrity and function were determined in vitro and in vivo. We found that endothelial cells have a limited capacity to internalize NETs via the receptor for advanced glycation endproducts. An overflow of the phagocytic capacity of endothelial cells for NETs resulted in the persistent extracellular presence of NETs, which rapidly altered endothelial cell–cell contacts and induced vascular leakage and transendothelial albumin passage through elastase-mediated proteolysis of the intercellular junction protein VE-cadherin. Furthermore, NET-associated elastase promoted the nuclear translocation of junctional β-catenin and induced endothelial-to-mesenchymal transition in cultured endothelial cells. In vivo, NETs could be identified in kidney samples of diseased MRL/lpr mice and patients with lupus nephritis, in whom the glomerular presence of NETs correlated with the severity of proteinuria and with glomerular endothelial-to-mesenchymal transition. Conclusions— These results indicate that an excess of NETs exceeds the phagocytic capacity of endothelial cells for NETs and promotes vascular leakage and endothelial-to-mesenchymal transition through the degradation of VE-cadherin and the subsequent activation of β-catenin signaling. Our data designate NET-associated elastase as a potential therapeutic target in the prevention of endothelial alterations in diseases characterized by aberrant NET release.

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Section: Glomerular Nets Are Associated With Proteinuria and Endmt Inmentioning

confidence: 99%

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Pieterse

Rother

Garsen

et al. 2017

ATVB

199

150

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“…Various post-translational modifications of cellular proteins occur during NETosis and the enhanced externalization of these proteins, combined with defective clearance, may promote disruptions in adaptive immunity that further drive SLE pathogenesis (117, 119, 120, 203). SLE NETs contain histone modifications that are also observed during apoptosis (203).…”

Section: Netosis-derived Post-translational Modifications In Slementioning

confidence: 99%

Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis

Mistry

Kaplan

2017

Clinical Immunology

170

137

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Nephritis is one of the most severe complications of systemic lupus erythematosus (SLE). One key characteristic of lupus nephritis (LN) is the deposition of immune complexes containing nucleic acids and/or proteins binding to nucleic acids and autoantibodies recognizing these molecules. A variety of cell death processes are implicated in the generation and externalization of modified nuclear autoantigens and in the development of LN. Among these processes, apoptosis, primary and secondary necrosis, NETosis, necroptosis, pyroptosis, and autophagy have been proposed to play roles in tissue damage and immune dysregulation. Cell death occurs in healthy individuals during conditions of homeostasis yet autoimmunity does not develop, at least in part, because of rapid clearance of dying cells. In SLE, accelerated cell death combined with a clearance deficiency may lead to the accumulation and externalization of nuclear autoantigens and to autoantibody production. In addition, specific types of cell death may modify autoantigens and alter their immunogenicity. These modified molecules may then become novel targets of the immune system and promote autoimmune responses in predisposed hosts. In this review, we examine various cell death pathways and discuss how enhanced cell death, impaired clearance, and post-translational modifications of proteins could contribute to the development of lupus nephritis.

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“…The results indicated that the modifications of histones are involved in the pathogenesis of SLE (25,26). Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps (NETs) in systemic lupus erythematosus (27). It was found that the histone acetyltransferases (HATs) and histone deacetylases (HDACs) were abnormal in patients with active SLE (25).…”

Section: Histone Modifications and Slementioning

confidence: 99%

Epigenetics in systemic lupus erythematosus

Xiao

Zuo

2015

Biomedical Reports

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Abstract. Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, with mechanisms that remain to be elucidated. Previous studies have proposed that genes and environments are required for lupus to develop and flare. It has been found that epigenetics have a significant influence on SLE. The present review will concentrate on epigenetics in SLE. There are a number of studies reporting that autoreactive T cells and B cells in patients with SLE have evidence of altered patterns of DNA methylation, modifications of histones and microRNA (miRNA). Long noncoding RNAs (lncRNAs) are another type of noncoding RNAs, which have an important role in epigenetics. lncRNAs may possibly become a new hotspot in SLE.

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Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus

Cited by 98 publications

References 26 publications

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis

Epigenetics in systemic lupus erythematosus

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