Antineutrophil properties of natural gingerols in models of lupus

Ali, Ramadan A.; Gandhi, Alex A.; Dai, Lipeng; Weiner, Julia; Estes, Shanea K.; Yalavarthi, Srilakshmi; Gockman, Kelsey; Sun, Duxin; Knight, Jason S.

doi:10.1172/jci.insight.138385

Cited by 26 publications

(27 citation statements)

References 57 publications

(64 reference statements)

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“…Since defibrotide suppressed antiphospholipid antibody-mediated NET formation in vitro, we were interested in whether it might also mitigate antiphospholipid antibody-accelerated NET formation and thrombosis in mice. To test this, we utilized an electrolytic IVC model to induce large-vein thrombosis (Figure 2A) (9,10). Administration of IgG isolated from patients with APS (pooled from 3 patients with CAPS), but not control IgG, increased thrombus length in C57BL/6 mice, which returned to baseline levels when defibrotide was administered at doses as low as 15 mg/kg (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

“…Levels of cAMP were then measured using the Bridge‐It cAMP Designer fluorescence assay kit (Mediomics catalog no. 122934) as instructed by the manufacturer and as we have done previously (10).…”

Section: Methodsmentioning

confidence: 99%

“…In vivo induction of venous thrombosis in mice. We used an electrolytic inferior vena cava (IVC) model that has been used previously by our group (9,10). After exposure of the IVC of mice, any lateral branches were ligated using 7-0 Prolene sutures.…”

Section: Qualitative Immunofluorescence Microscopymentioning

confidence: 99%

“…Neutrophils isolated from patients with APS have a diminished threshold for spontaneous NET formation, while neutrophils from healthy volunteers can be activated to release NETs by exposure to APS serum or purified antiphospholipid antibodies (7). In mouse models of antiphospholipid antibody–accelerated large vein thrombosis, treatments that counteract NETs such as neutrophil depletion (8), administration of intravenous deoxyribonuclease (8), agonism of neutrophil adenosine A 2A receptors (9), boosting neutrophil cyclic AMP (cAMP) levels (10), and interfering with adhesive interactions between neutrophils and the endothelium (11) are all protective.…”

Section: Introductionmentioning

confidence: 99%

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Defibrotide Inhibits Antiphospholipid Antibody–Mediated Neutrophil Extracellular Trap Formation and Venous Thrombosis

Ali

Estes

Gandhi

et al. 2022

Arthritis & Rheumatology

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Objective. Defibrotide is a heterogenous mixture of polyanionic oligonucleotides currently approved for treatment of transplant-associated venoocclusive disease. While defibrotide has a known role in limiting endothelial cell activation, some studies have also demonstrated anti-leukocyte properties. In a recent study, we found that neutrophil extracellular traps (NETs) play a role in the thrombotic complications of antiphospholipid syndrome (APS). In the present study, we investigated the hypothesis that defibrotide might act to mitigate APS-relevant NET formation in vitro and in mouse models.Methods. We used in vitro assays and a mouse model to determine the mechanisms by which defibrotide inhibits NET formation and venous thrombosis in APS.Results. At doses ranging from 1 to 10 μg/ml, defibrotide significantly suppressed NET formation from control neutrophils stimulated with IgG isolated from patients with APS. Defibrotide increased levels of intracellular cyclic AMP in neutrophils, and its suppressive effects on NET formation were mitigated by blocking adenosine A 2A receptor or by inhibiting the cyclic AMP-dependent kinase protein kinase A. Defibrotide at doses ranging from 15 to 150 mg/kg/day inhibited NET formation and venous thrombosis in a model of antiphospholipid antibody-accelerated thrombosisan effect that was reduced in adenosine A 2A receptor-knockout mice.Conclusion. This study is the first to demonstrate mechanisms by which defibrotide counteracts neutrophilmediated thrombotic inflammation inherent to APS.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Qualitative Immunofluorescence Microscopymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Defibrotide Inhibits Antiphospholipid Antibody–Mediated Neutrophil Extracellular Trap Formation and Venous Thrombosis

Ali

Estes

Gandhi

et al. 2022

Arthritis & Rheumatology

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“…Indeed, NETs contribute to APS pathophysiology as amplifiers of inflammation and thrombosis. Indeed, the aPL administration increased serum NET levels, which returned to baseline when mice were treated with 6-gingerol [ 65 ].…”

Section: Antioxidant Treatment In Aps Patients: the State Of The Artmentioning

confidence: 99%

Oxidative Stress in the Pathogenesis of Antiphospholipid Syndrome: Implications for the Atherothrombotic Process

et al. 2021

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Atherothrombosis is a frequent complication of the clinical history of patients with antiphospholipid syndrome (APS). Both atherothrombosis and APS are characterized by increased oxidative stress. Oxidative modifications are implicated in the formation of antiphospholipid antibodies, which in turn may favour the oxidative imbalance by increasing the production of reactive oxidant species (ROS) or by a direct interaction with pro-oxidant/antioxidant enzymes. As a result of these processes, APS patients suffer from an oxidative imbalance that may contribute to the progression of the atherosclerotic process and to the onset of ischemic thrombotic complications. The aim of this review is to describe mechanisms implicated in the formation of ROS in APS patients and their involvement in the atherothrombotic process. We also provide an overview of potential therapeutic approaches to blunt oxidative stress and to prevent atherothrombotic complications in these patients.

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Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome

Knight

Kanthi

2022

Semin Immunopathol

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Antiphospholipid syndrome (APS) is an autoimmune thrombophilia propelled by circulating antiphospholipid antibodies that herald vascular thrombosis and obstetrical complications. Antiphospholipid antibodies recognize phospholipids and phospholipid-binding proteins and are not only markers of disease but also key drivers of APS pathophysiology. Thrombotic events in APS can be attributed to various conspirators including activated endothelial cells, platelets, and myeloid-lineage cells, as well as derangements in coagulation and fibrinolytic systems. Furthermore, recent work has especially highlighted the role of neutrophil extracellular traps (NETs) and the complement system in APS thrombosis. Beyond acute thrombosis, patients with APS can also develop an occlusive vasculopathy, a long-term consequence of APS characterized by cell proliferation and infiltration that progressively expands the intima and leads to organ damage. This review will highlight known pathogenic factors in APS and will also briefly discuss similarities between APS and the thrombophilic coagulopathy of COVID-19.

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Antineutrophil properties of natural gingerols in models of lupus

Cited by 26 publications

References 57 publications

Defibrotide Inhibits Antiphospholipid Antibody–Mediated Neutrophil Extracellular Trap Formation and Venous Thrombosis

Defibrotide Inhibits Antiphospholipid Antibody–Mediated Neutrophil Extracellular Trap Formation and Venous Thrombosis

Oxidative Stress in the Pathogenesis of Antiphospholipid Syndrome: Implications for the Atherothrombotic Process

Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome

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