Abstract
Ginger is known to have antiinflammatory and antioxidative effects and has traditionally been used as an herbal supplement in the treatment of various chronic diseases. Here, we report antineutrophil properties of 6-gingerol, the most abundant bioactive compound of ginger root, in models of lupus and antiphospholipid syndrome (APS). Specifically, we demonstrate that 6-gingerol attenuates neutrophil extracellular trap (NET) release in response to lupus- and APS-relevant stimuli through a mechanism that is at least partially dependent on inhibition of phosphodiesterases. At the same time, administration of 6-gingerol to mice reduces NET release in various models of lupus and APS, while also improving other disease-relevant endpoints, such as autoantibody formation and large-vein thrombosis. In summary, this study is the first to our knowledge to demonstrate a protective role for ginger-derived compounds in the context of lupus. Importantly, it provides a potential mechanism for these effects via phosphodiesterase inhibition and attenuation of neutrophil hyperactivity.
Highlights
Systemic lupus erythematosus is the prototypical systemic autoimmune disease, characterized by antinuclear autoantibodies and circulating immune complexes
We have shown that patients with Antiphospholipid syndrome (APS) have higher levels of cell-free DNA and neutrophil extracellular trap (NET) in plasma and that their neutrophils are prone to spontaneous NETosis as compared with healthy controls [12]
We first tested the efficacy of 3 related compounds, 6-gingerol, 8-gingerol, and 10-gingerol, for their ability to suppress NETosis by control neutrophils
Summary
Systemic lupus erythematosus (lupus) is the prototypical systemic autoimmune disease, characterized by antinuclear autoantibodies and circulating immune complexes. Neutrophils release neutrophil extracellular traps (NETs) — tangles of chromatin and microbicidal proteins expelled from neutrophils in response to both infectious and sterile stimuli [5, 6] — which have garnered much recent attention as amplifiers of inflammation and thrombosis in autoimmune diseases such as lupus and APS [7,8,9,10]. We have shown that patients with APS have higher levels of cell-free DNA and NETs in plasma and that their neutrophils are prone to spontaneous NETosis as compared with healthy controls [12]. APL isolated from patients with APS can trigger healthy control neutrophils to release NETs [12], while potentiating thrombosis in vivo in neutrophil- and NET-dependent fashion [13]. Lupus-associated autoantibodies, including anti-ribonucleoprotein (anti-RNP) [14], aPL [12], and anti– double-stranded DNA (anti–dsDNA) [18], accelerate NETosis, thereby setting up a vicious cycle
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