Altered Mitochondrial Homeostasis during Systemic Lupus Erythematosus Impairs Neutrophil Extracellular Trap Formation Rendering Neutrophils Ineffective at Combating Staphylococcus aureus

2021 ◽  
pp. ji2100752
Author(s):  
Andrew J. Monteith ◽  
Jeanette M. Miller ◽  
Jonathan M. Williams ◽  
Kelsey Voss ◽  
Jeffrey C. Rathmell ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Staphylococcus Aureus ◽  
Lupus Erythematosus ◽  
Neutrophil Extracellular Trap ◽  
Systemic Lupus ◽  
Mitochondrial Homeostasis ◽  
Trap Formation ◽  
Extracellular Trap

scholarly journals Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus

2019 ◽  
Vol 78 (10) ◽  
pp. 1363-1370 ◽  
Author(s):  
Lina Odqvist ◽  
Zala Jevnikar ◽  
Rebecca Riise ◽  
Lisa Öberg ◽  
Magdalena Rhedin ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Genetic Alterations ◽  
Genetic Variations ◽  
Negative Regulator ◽  
Systemic Lupus ◽  
Trap Formation ◽  
Autoimmune Pathology ◽  
Extracellular Trap

ObjectivesGenetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis.MethodsCRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926.ResultsGenetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes.ConclusionsWe propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.

scholarly journals RB137 recognizes LL37 in neutrophil-extracellular trap-like (NET) structures in systemic lupus erythematosus and rheumatoid arthritis inflamed tissues by immunofluorescence in histological sections

2020 ◽  
Vol 3 (4) ◽  
pp. e235
Author(s):  
Roberto Lande ◽  
Stefano Alivernini ◽  
Barbara Tolusso ◽  
Francesca Spadaro ◽  
Mario Falchi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Neutrophil Extracellular Trap ◽  
Human Tissues ◽  
Systemic Lupus ◽  
Native Form ◽  
Recombinant Monoclonal Antibody ◽  
Health And Disease ◽  
Extracellular Trap

Besides being a natural antibiotic, the human cathelicidin LL37, produced by epithelial cells and neutrophils, is an important immune-modulator. LL37 alone, or in complex with DNA, can activate inflammatory pathways in psoriasis, Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). In this work, we describe the capacity of the recombinant monoclonal antibody RB137, previously shown to specifically recognize LL37 in its native form by ELISA, to detect LL37 by immunofluorescence in human tissues derived from SLE and RA patients. In these tissues, LL37 decorates DNA filaments resembling neutrophil-extracellular-trap (NET) structures. This antibody represents a valuable tool to detect the presence, the native state and the exact localization of LL37 in human tissues in health and disease.

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