A single nucleotide polymorphism in the<i>NCF1</i>gene leading to reduced oxidative burst is associated with systemic lupus erythematosus

Olsson, Lina; Johansson, Åsa; Gullstrand, Birgitta; Jönsen, Andreas; Saevarsdóttir, Saedís; Rönnblom, Lars; Leonard, Dag; Wetterö, Jonas; Sjöwall, Christopher; Svenungsson, Elisabet; Gunnarsson, Iva; Bengtsson, Anders; Holmdahl, Rikard

doi:10.1136/annrheumdis-2017-211287

Cited by 113 publications

(116 citation statements)

References 35 publications

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“…It causes joint pain and degradation, and, if left untreated, can lead to cardiovascular disease and other comorbidities that result in disability and decreased quality of life. RA is in part dependent on genetics; among the genes that are reported to contribute to the development of RA are the major histocompatibility complex (MHC) class II region, protein tyrosine phosphatase N22, and neutrophil cytosolic factor 1 (NCF‐1) . NCF‐1 has an essential role in the NADPH oxidase 2 (NOX‐2) complex, which in turn has an important role in the defense against pathogens through the production of reactive oxygen species (ROS).…”

mentioning

confidence: 99%

Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells

Hagert

Sareila

Kelkka

et al. 2018

Arthritis & Rheumatology

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mentioning

confidence: 99%

Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells

Hagert

Sareila

Kelkka

et al. 2018

Arthritis & Rheumatology

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“…The importance of ROS in the regulation of inflammation also gains support from our earlier studies in which we through positional cloning of a disease linked genetic polymorphism, have identified Ncf1 (encoding for the p47 phox subunit of the NADPHoxidase complex) as a disease-associated gene [19] and the molecular basis being linked to a compromised ROS production [20]. Similarly, polymorphism of Ncf1 plays a role in human autoimmune diseases [21,22], and in animal models, it has been shown to be of importance for disease severity of arthritis, psoriasis, colitis, and lupus, reviewed in [14,23]. It is apparent from both pharmacological and genetic deletion studies, that FPRs have multiple roles in diseases conditions associated with a dysregulated inflammation.…”

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confidence: 85%

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2-complex

Lind

Holmdahl

Olofsson

et al. 2020

Preprint

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Two formyl peptide receptors (FPR1 and FPR2), abundantly expressed by neutrophils, regulate both pro-inflammatory tissue recruitment of neutrophils and resolution of inflammatory reactions. This dual functionality of the FPRs, opens for a possibility to develop receptor selective therapeutics as mechanism for novel anti-inflammatory treatments. In line with this, high throughput screening studies have identified numerous FPR ligands belonging to different structural classes, but a potent FPR1 agonist with defined biased signaling and functional selectivity has not yet been reported. In this study, we used an FPR1 selective small compound agonist (RE) that represents a chemical entity developed from NOX2 activators identified from our earlier screening studies (WO2012127214). This FPR1 agonist potently activates neutrophils to produce reactive oxygen species (ROS, EC50 ~1 nM), whereas it is a weaker chemoattractant than the prototype FPR1 agonist fMLF. At the signaling level, RE has a strong bias towards the PLC-PIP2-Ca 2+ pathway and ERK1/2 activation but away from β-arrestin recruitment and the ability to recruit neutrophils chemotactically. In addition, FPR1 when activated by RE could crossregulate other receptor-mediated neutrophil functions. In comparison to the peptide agonist fMLF, RE is more resistant to oxidization-induced inactivation by the MPO-H2O2-halide system. In summary, this study describes as a novel FPR1 agonist displaying a biased signaling and functional selectivity when activating FPR1 in human blood neutrophils. RE could possibly be a useful tool compound not only for further mechanistic studies of the regulatory role of FPR1 in inflammation in vitro and in vivo, but also for developing FPR1specific drug therapeutics.

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“…We previously showed that a single nucleotide polymorphism in Ncf1, resulting in loss-offunction amino acid substitution, led to an increased risk of developing arthritis [3,4]. Superoxide defect by mutations in Ncf1 gene was subsequently shown to cause arthritis and lupus in mice [5,6], and in humans [7][8][9][10].…”

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confidence: 99%

Independent and inter-dependent immunoregulatory effects of NCF1 and NOS2 in experimental autoimmune encephalomyelitis

Zhong

Yau

Holmdahl

2020

J Neuroinflammation

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Background: Increasing evidence has suggested that a single nucleotide polymorphism in the Ncf1 gene is associated with experimental autoimmune encephalomyelitis (EAE). However, the mechanisms of NCF1-induced immunoregulatory effects remain poorly understood. In this study, we focus on NCF1 deficiency-mediated effects on EAE in NOS2 dependent and independent ways. Methods: To determine the effects of NCF1 and NOS2 during EAE development, we have established recombinant mouse strains deficient at NCF1 and/or NOS2 in a crossbreeding system. Different strains allow us to examine the entire course of the disease in the Nos2-null mice bearing a Ncf1 gene that encodes a mutated NCF1, deficient in triggering oxidative burst, after immunization with recombinant myelin oligodendrocyte glycoprotein (MOG) 79-96 peptides. The peptide-induced innate and adaptive immune responses were analyzed by flow cytometry.Results: NCF1-deficient mice developed a reduced susceptibility to EAE, whereas NCF1-NOS2 double-deficient mice developed an enhanced EAE, as compared with NOS2-deficient mice. Flow cytometry analyses show that double deficiencies resulted in an increase of neutrophils in the spleen, accompanied with higher release of interleukin-1β in neutrophils prior to EAE onset. The additional deficiency in NCF1 had no added effect on either interleukin-17 or interferon-γ secretion of T cells during the priming phase.Conclusions: These studies show that NCF1 and NOS2 interact to regulate peptide-induced EAE.

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A single nucleotide polymorphism in theNCF1gene leading to reduced oxidative burst is associated with systemic lupus erythematosus

Abstract: These results clearly demonstrate that a genetically controlled reduced production of ROS increases the risk of developing SLE and confirm the hypothesis that ROS regulate chronic autoimmune inflammatory diseases.

Cited by 113 publications

References 35 publications

Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells

Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2-complex

Independent and inter-dependent immunoregulatory effects of NCF1 and NOS2 in experimental autoimmune encephalomyelitis

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