Ginger is known to have anti-inflammatory and anti-oxidative properties that have led to its popular use as a herbal supplement for treating inflammatory diseases. Studies by a team at the University of Michigan now suggest that 6-gingerol, the main bioactive compound in ginger root, has therapeutic effects against certain autoimmune diseases, including lupus and antiphospholipid syndrome (APS), in mice, by countering the release of neutrophil extracellular traps (NETs). Describing the results of their studies in JCI Insight, first author Ramadan Ali, PhD, postdoctoral research fellow, and colleagues say their findings point to the potential use of ginger as a supplement to help prevent autoimmune and other disorders in those at risk. “While it is unlikely that ginger extract or 6-gingerol would find a role as a primary therapeutic in individuals with active disease, one wonders if future studies might administer ginger supplements to individuals at high risk for autoimmune conditions and/or cardiovascular disease (for example, individuals with autoantibodies who have yet to have clinical events, or patients with cardiovascular risk factors).” The team’s published paper is titled “Anti-neutrophil properties of natural gingerols in models of lupus.”

Systemic lupus erythematosus (lupus) is a prototypical systemic autoimmune disease that can impact just about any organ in the body, while the closely related thromboinflammatory disease, APS, causes blood clots, and can lead to pregnancy loss, the authors noted. APS can occur on its own, or in association with lupus. For their studies, the team looked at both these conditions, as they can both cause widespread inflammation, and damage organs over time.

Ginger has long been used in herbal medicine for treating ailments including chronic conditions such as asthma and arthritis. “It has been suggested that ginger may mediate its anti-inflammatory effects by reducing levels of pro-inflammatory cytokines, as well as tempering synthesis and secretion of chemokines at sites of inflammation,” the authors wrote. The most abundant bioactive compound in fresh ginger is 6-gingerol. While ginger has long been perceived to have anti-inflammatory effects, these have not been investigated in the context of lupus and APS, the authors stated. “Of particular note, no attention has been given to the effects of gingerols on activation and function of neutrophils as thromboinflammatory mediators in lupus and APS.”

NETs—tangles of chromatin and microbicidal proteins that are expelled from neutrophils in response to both infectious and sterile stimuli—and have garnered what the authors pointed out is “… much recent attention as amplifiers of inflammation and thrombosisin autoimmune diseases such as lupus and APS.” Ali further explained, “Neutrophil extracellular traps, or NETs, come from white blood cells called neutrophils …These sticky spider-web like structures are formed when autoantibodies interact with receptors on the neutrophil’s surface.”

Given evidence that gingerols may impact on certain biochemical pathways that the investigators had recently characterized in lupus and APS neutrophils, they “… sought to determine the extent to which ginger-derived compounds might function as a natural suppressor of aberrant neutrophil hyperactivity.” Their study question was thus, “will the anti-inflammatory properties of ginger extend to neutrophils, and specifically, can this natural medicine stop neutrophils from making NETs that contribute to disease progression?” Ali said. “This preclinical study in mice offers a surprising and exciting, ‘yes’.”

According to Ali, the NET webs play an important role in the pathogenesis of lupus and APS, where they trigger autoantibody formation and contribute to blood vessel clotting and damage.

The scientists’ studies in mouse models of either APS or lupus, showed that 6-gingerol prevented neutrophil extracellular trap release, which is triggered by the autoantibodies that these diseases produce. They found that mice given 6-gingerol had lower levels of NETs. The tendency to make clots was also drastically reduced, and 6-gingerol appeared to inhibit neutrophil phosphodiesterase (PDE) enzymes, which in turn reduced neutrophil activation. “Mechanistically, we found that the effects of 6-gingerol on neutrophils are at least partially attributable to its ability to inhibit PDE activity,” they wrote. “Furthermore, 6-gingerol suppressed the production of pro-inflammatory cytokines, such as TNF-α and IFN-γ, similar to PDE4 inhibitors …”

But the most surprising find of all was that regardless of whether they had APS or lupus, mice given the ginger compound had reduced autoantibodies, suggesting inhibition of the inflammatory cycle of autoantibodies stimulating NETs, which then stimulates more autoantibodies, was inhibited.

“Through my years of medical training I wasn’t taught much about supplements, but it’s something that so many patients ask me about,” said study co-author and rheumatologist Jason Knight, MD. “When Ramadan brought the concept to me, I was enthusiastic to pursue it in my lab, as I knew it would matter to them. Sometimes our patients give us really good ideas!”

While the investigators’ study was carried out in mouse models, Ali and Knight think the preclinical data showing that 6-gingerol has anti-neutrophil properties that may protect against autoimmune disease progression, should encourage clinical trial development. “As for basically all treatments in our field, one size does not fit all. But, I wonder if there is a subgroup of autoimmune patients with hyperactive neutrophils who might benefit from increased intake of 6-gingerol,” Knight said. “It will be important to study neutrophils before and after treatment so we can determine the subgroup most likely to see benefit.”

As the authors concluded, “… this study is the first to demonstrate a protective role for ginger-derived compounds in the context of lupus, and importantly provides a potential mechanism for these effects via phosphodiesterase inhibition and attenuation of neutrophil hyperactivity … Here, we have revealed anti-neutrophil properties of 6-gingerol that may have protective effects in disease states such as lupus and APS. In vivo, we characterized two lupus-relevant inflammatory models and found that 6-gingerol reduced NETosis in both. Beyond inhibition of NETosis, we also saw positive effects of disease phenotypes such as autoantibody formation and thrombosis, and observed that 6-gingerol behaved very similarly to a synthetic PDE4 inhibitor.”

The scientists said it is unlikely that the bioactive compound itself would be suitable as the primary therapy for someone with active APS or lupus, but are interested to see if the natural supplement may help those at high risk for disease development. “Those that have autoantibodies, but don’t have activated disease, may benefit from this treatment if 6-gingerol proves to be a protective agent in humans as it does in mice,” noted Ali, who is passionate about natural medicine research for rheumatic diseases. “Patients with active disease take blood thinners, but what if there was also a natural supplement that helped reduce the amount of clots they produce? And what if we could decrease their autoantibodies?”

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