Background/Purpose: 6-gingerol, the major bioactive compound of ginger root, is known to have anti-inflammatory and anti-oxidative effects. Indeed, ginger has been employed for millennia as an herbal supplement in the treatment of inflammatory diseases. Our group recently revealed that 6-gingerol prevents neutrophil extracellular trap (NET) release triggered by either ribonucleoprotein (RNP)/anti-RNP complexes or antiphospholipid antibodies (aPL). Here, we sought to further elucidate the mechanism by which 6-gingerol suppresses NET release, as well as to test its efficacy in lupus-relevant mouse models.

Methods: For in vitro studies, human neutrophils were prepared from healthy volunteers and stimulated with either immune complexes from lupus patients (RNP/anti-RNP) or total IgG fractions from primary APS patients (aPL). Stimulation was in the presence or absence of 6-gingerol and NET release was quantified via the enzymatic activity of NET-associated myeloperoxidase. Phosphodiesterase 4 (PDE4) activity and cyclic AMP (cAMP) levels were measured by chromogenic assays. In vivo, 6-gingerol (10 mg/kg/day) was tested in two models characterized by accelerated NET release: TLR7 agonist-induced lupus (BALB/c mice) and aPL-accelerated inferior vena cava thrombosis (C57BL/6 mice).

Results: As in our previous study, 6-gingerol completely neutralized RNP/anti-RNP- and aPL-mediated NET release at low micromolar concentrations. We further explored mechanisms of aPL-mediated NET release and found that 6-gingerol suppresses normal PDE4 activity, and thereby raises intracellular levels of cAMP. Indeed, the suppressive effects of 6-gingerol could be mitigated by blocking activity of the cAMP-responsive protein kinase A complex. Administration of 6-gingerol to TLR7 agonist-treated mice (model of lupus) resulted in a marked reduction in plasma NET levels, as well as anti-double-stranded DNA and anti-beta-2 glycoprotein I autoantibodies. In a model of APS, 6-gingerol neutralized the acceleration of large-vein thrombosis by human aPL; importantly levels of plasma NET were reduced in the same model.

Conclusion: We demonstrate for the first time that the natural compound 6-gingerol attenuates lupus-relevant NET release in vitro through a mechanism that at least partially depends on inhibition of PDE4. At the same time, administration of 6-gingerol to mice reduces NET release in models of lupus and APS, while also attenuating other disease-relevant activities such as autoantibody formation and large-vein thrombosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/potent-anti-neutrophil-properties-of-the-natural-compound-6-gingerol-in-models-of-lupus-and-antiphospholipid-syndrome/