Neutrophil homeostasis through ginger supplementation in SLE

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which the immune system mistakenly attacks the body, leading to fatigue, pain, and damage to organs such as the kidneys, skin, and joints. Even when SLE appears clinically stable, underlying immune activation can persist, harming tissues and reducing quality of life. Recent research has found that a type of immune cell called the neutrophil plays an important role in driving inflammation in SLE by releasing spider web-like structures known as neutrophil extracellular traps (NETs), which trigger further harmful immune reactions. Safe and accessible ways to calm these neutrophil-mediated immune pathways are urgently needed. Our preliminary studies have found that ginger, a widely used dietary supplement, contains natural bioactive compounds (i.e., phytochemicals) that reduce neutrophil activation by increasing intracellular levels of the calming signal cAMP. To date, our peer-reviewed research framing this proposal has included extensive laboratory and animal experiments, as well as a study of healthy volunteers. Here, we plan to test whether ginger supplementation can reduce harmful neutrophil activation in people with SLE. Participants will receive ginger or a placebo in a controlled clinical study, and we will measure changes in blood-based immune cell activation and inflammation-related markers. At this stage, the research will not test whether ginger directly treats SLE symptoms. Rather, it will determine whether ginger engages key immune pathways and is safe and feasible for the future larger studies that we anticipate will be needed to confirm its clinical benefits. Ultimately, this work could pave the way for simple, patient-friendly, lifestyle-based strategies to complement existing lupus treatments.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which persistent immune activation leads to fatigue, impaired quality of life, and organ damage, even among individuals with low clinical disease activity. While the role of adaptive immune dysfunction has long been emphasized in explaining SLE pathogenesis, a growing body of evidence identifies innate immune pathways, including exaggerated neutrophil activation and neutrophil extracellular trap formation (NETosis), as important drivers of inflammatory signaling, immune amplification, and tissue injury. Proinflammatory NETs bolster type I interferon-associated pathways, activate complement, expose autoantigens, and sustain immune complex-mediated inflammation. Despite the emerging importance of NETs, few safe, scalable strategies exist to directly modulate neutrophil activity in individuals living with SLE. Ginger-derived phytochemicals, including 6-gingerol, inhibit phosphodiesterase activity, increasing intracellular cyclic AMP (cAMP) and thereby suppressing neutrophil activation. We have already demonstrated that ginger-derived compounds reduce NETosis in vitro and in multiple lupus-relevant mouse models. Furthermore, in a peer-reviewed pilot study of healthy volunteers, we found that one week of ginger supplementation was sufficient to increase neutrophil cAMP and reduce stimulated NETosis ex vivo. Our central hypothesis is that ginger supplementation will engage a predefined neutrophil regulatory pathway in patients with SLE, thereby suppressing NETosis and attenuating downstream immune amplification inherent to lupus pathogenesis. To test this hypothesis, we propose a randomized, double-blind, placebo-controlled, crossover mechanistic clinical study of ginger supplementation in patients with SLE who are positive for anti-double-stranded DNA antibodies and on stable background therapy. Consistent with the goals of this Lupus Research Alliance Mechanistic Clinical Award, the key outcomes will be molecular, cellular, and immunologic (i.e., mechanistic), rather than focused on clinical efficacy. Aim 1 will determine whether ginger supplementation engages neutrophil cAMP signaling and suppresses NETosis in patients with SLE. Aim 2 will establish feasibility and safety to inform future lifestyle-based interventional studies for SLE.