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Clinical Implications of Excessive Neutrophil Extracellular Trap Formation in Renal Autoimmune Diseases.

ABSTRACT: Neutrophil extracellular traps (NETs) are extracellular DNA structures covered with antimicrobial peptides, danger molecules, and autoantigens that can be released by neutrophils. NETs are an important first-line defense mechanism against bacterial, viral, fungal, and parasitic infections, but they can also play a role in autoimmune diseases. NETs are immunogenic and toxic structures that are recognized by the autoantibodies of patients with antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) (i.e., against myeloperoxidase or proteinase-3) and systemic lupus erythematosus (SLE) (i.e., against double-stranded DNA, histones, or nucleosomes). There is cumulating preclinical and clinical evidence that both excessive formation and impaired degradation of NETs are involved in the pathophysiology of AAV and SLE. These autoimmune diseases give rise to 2 clinically and pathologically distinct forms of glomerulonephritis (GN), respectively, crescentic pauci-immune GN and immune complex-mediated GN. Therefore, it is relevant to understand the different roles NET formation can play in the pathophysiology of these most prevalent renal autoimmune diseases. This review summarizes the current concepts on the role of NET formation in the pathophysiology of AAV and SLE, and provides a translational perspective on the clinical implications of NETs, such as potential therapeutic approaches that target NET formation in these renal autoimmune diseases.

SUBMITTER: van Dam LS

PROVIDER: S-EPMC6365354 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Clinical Implications of Excessive Neutrophil Extracellular Trap Formation in Renal Autoimmune Diseases.

van Dam Laura S LS Rabelink Ton J TJ van Kooten Cees C Teng Y K Onno YKO

Kidney international reports 20181119 2

Neutrophil extracellular traps (NETs) are extracellular DNA structures covered with antimicrobial peptides, danger molecules, and autoantigens that can be released by neutrophils. NETs are an important first-line defense mechanism against bacterial, viral, fungal, and parasitic infections, but they can also play a role in autoimmune diseases. NETs are immunogenic and toxic structures that are recognized by the autoantibodies of patients with antineutrophil cytoplasmic antibodies-associated vascu ...[more]

PMID: 30775617

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Project description:Neutrophils undergo a unique form of cell death to generate neutrophil extracellular traps (NETs). It is well established that citrullination of histones (e.g., CitH3) facilitates chromatin decondensation during NET formation (NETosis), particularly during calcium-induced NETosis that is independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activation. However, the importance of other forms of histone modifications in NETosis has not been established. We considered that acetylation of histones would also facilitate NETosis. To test this hypothesis, we induced NOX-dependent NETosis in human neutrophils with phorbol myristate acetate or lipopolysaccharide (from Escherichia coli 0128), and NOX-independent NETosis with calcium ionophores A23187 or ionomycin (from Streptomycesconglobatus) in the presence or absence of two pan histone deacetylase inhibitors (HDACis), belinostat and panobinostat (within their half maximal inhibitory concentration (IC50) range). The presence of these inhibitors increased histone acetylation (e.g., AcH4) in neutrophils. Histone acetylation was sufficient to cause a significant increase (~20%) in NETosis in resting neutrophils above baseline values. When acetylation was promoted during NOX-dependent or -independent NETosis, the degree of NETosis additively increased (~15⁻30%). Reactive oxygen species (ROS) production is essential for baseline NETosis (mediated either by NOX or mitochondria); however, HDACis did not promote ROS production. The chromatin decondensation step requires promoter melting and transcriptional firing in both types of NETosis; consistent with this point, suppression of transcription prevented the NETosis induced by the acetylation of histones. Collectively, this study establishes that histone acetylation (e.g., AcH4) promotes NETosis at baseline, and when induced by both NOX-dependent or -independent pathway agonists, in human neutrophils. Therefore, we propose that acetylation of histone is a key component of NETosis.

Dataset Information

Clinical Implications of Excessive Neutrophil Extracellular Trap Formation in Renal Autoimmune Diseases.

Publications

Clinical Implications of Excessive Neutrophil Extracellular Trap Formation in Renal Autoimmune Diseases.

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