Background/Purpose: Recent studies have revealed a role for neutrophils in the pathogenesis of lupus and antiphospholipid syndrome (APS). Indeed, neutrophils are activated by various disease-relevant stimuli including ribonucleoprotein (RNP)/anti-RNP complexes and antiphospholipid antibodies (aPL) to release tangles of DNA and protein known as neutrophil extracellular traps (NETs). Ginger is known to have anti-inflammatory and anti-oxidative effects, and has traditionally been used as an herbal supplement in the treatment of inflammatory diseases. Here, we hypothesized that compounds isolated from ginger might mitigate NET release (NETosis) in response to lupus- and APS-relevant stimuli.

Methods: Control human neutrophils were prepared from healthy volunteers and stimulated with phorbol 12-myristate 13-acetate (PMA); E. coli lipopolysaccharide (LPS); total IgG fractions prepared from primary APS patients (aPL); or RNP/anti-RNP complexes prepared from lupus patients. Stimulation was in the presence of various bioactive compounds derived from ginger root. NETosis was quantified via chromogenic measurement of the enzymatic activity of NET-associated myeloperoxidase.

Results: So-called “gingerols” are the major bioactive compounds of ginger root. We first tested the efficacy of three related compounds, 6-gingerol, 8-gingerol, and 10-gingerol, for their ability to suppress NETosis by control neutrophils (of these compounds, 6-gingerol is the most abundant in ginger root). At doses ranging from 1 to 10 micromolar, both 6- and 8-gingerol completely neutralized aPL- and LPS-triggered NETosis, while 10-gingerol reduced NETosis by about 75%. 6-gingerol also effectively suppressed RNP/anti-RNP-induced NETosis at low micromolar concentrations. Interestingly, none of the compounds were efficacious against PMA-induced NETosis. Mechanistically, we reasoned that gingerols might suppress NETosis by preventing the neutrophil oxidative burst, as reactive oxygen species (ROS) are required for most forms of NETosis. Interestingly, aPL, LPS, and PMA all triggered significant hydrogen peroxide production by neutrophils, but gingerols only neutralized peroxide elicited by aPL and LPS.

Conclusion: We demonstrate for the first time that various natural gingerols found in ginger root can attenuate NET release and ROS production in response to various lupus-relevant stimuli (but not PMA) in vitro. Studies are underway to determine the extent to which these natural compounds may mitigate NET release, endothelial dysfunction, and venous thrombosis in mouse models of lupus and APS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/natural-gingerols-inhibit-neutrophil-extracellular-trap-release-elicited-by-lupus-autoantibodies/