Lupus is a well-known systemic autoimmune disease characterized by autoantibodies targeting nuclear components, leading to the formation of immune complexes that deposit in organs, causing damage.
APS, on the other hand, can manifest as a standalone autoimmune disease or in conjunction with lupus. It is primarily characterized by abnormal activation of the innate immune system and vascular cells, significantly increasing the risk of thrombosis in blood vessels of varying sizes.
NETosis involves neutrophils expelling their nuclear chromatin in the form of web-like structures decorated with potentially harmful granule-derived proteins.
Excessive NETosis fuels inflammatory and thrombotic processes, contributing to end organ damage over time and playing a role in the pathogenesis of many autoimmune diseases, including APS and lupus. Recent studies have shown that heightened NETosis can break adaptive immune tolerance, leading to the formation of autoantibodies.
Additionally, disease-associated autoantibodies can further stimulate NETosis, creating a vicious cycle. Importantly, research has also demonstrated the significance of neutrophils and NETs in the thrombo-inflammatory manifestations of diseases, including COVID-19.
Efforts to counteract NETosis have shown promise in mitigating the progression of autoimmune diseases. These strategies include neutrophil depletion, the use of deoxyribonuclease, and adenosine receptor agonists. One intriguing avenue of exploration in the quest to restrain NETosis is the use of natural herbs with anti-inflammatory properties. One such herb is ginger, which contains a bioactive compound known as 6-gingerol.
The Role of Ginger in Modulating Neutrophil Activity and NETosis
Previous research had highlighted the potential of purified 6-gingerol to inhibit neutrophil phosphodiesterase (PDE) activity, increasing intracellular cyclic AMP (cAMP) levels, and thus countering neutrophil hyperactivity in mouse models of APS and lupus. These findings were promising, but they were based on intraperitoneal injections of purified 6-gingerol.
To better understand the potential of ginger in humans, a study was conducted using orally administered ginger extract and involving healthy individuals. The aim was to investigate the effects of ginger on neutrophil activity and NETosis, laying the foundation for potential clinical trials in patients with NET-driven autoimmune diseases.
The Study: Ginger’s Impact on Neutrophil Activity and NETosis
- Ginger Reduces NETosis in Mouse Models: In mouse models of APS and lupus, oral consumption of a ginger extract, either through oral gavage or mixed with chow, resulted in reduced NETosis. This reduction was accompanied by improvements in disease-related outcomes, such as decreased thrombosis in APS and decreased autoantibody formation in lupus.
- Ginger Increases Neutrophil cAMP Levels: In two separate cohorts of healthy humans, daily consumption of a ginger supplement led to a neutrophil-specific increase in cAMP levels without affecting peripheral blood mononuclear cells (PBMC) cAMP. Elevated neutrophil cAMP levels were associated with a decrease in stimulated NETosis and circulating NET levels following ginger consumption.
- Mechanistic Insights: The study found that the solubilized ginger extract antagonized neutrophil PDE activity, increasing intracellular cAMP levels in neutrophils and reducing NETosis in human neutrophils in vitro. This aligns with previous studies indicating that ginger extracts, particularly 6-gingerol, act as inhibitors of cAMP-specific PDE activity. Importantly, the suppressive effects of ginger on NETosis could be reversed by blocking PKA activity, a key downstream kinase in the cAMP-dependent pathway.
Implications and Future Directions
The findings from this study are significant as they suggest that the properties of ginger observed in animal models and in vitro experiments extend to humans. This study utilized a commercially available whole-ginger extract with high concentrations of gingerols, providing a potential basis for further research. Various ginger supplements are available on the market, and their bioavailability and efficacy may differ, which necessitates further investigation.
While these results are promising, it’s important to note that the impact of ginger supplementation on neutrophils in patients with inflammatory diseases such as APS and lupus has not yet been tested. Additionally, the potential effects of ginger on the ability of neutrophils to respond to infections should be explored in future studies.
Furthermore, although some clinical trials have suggested potential benefits of ginger supplementation in conditions like arthritis and thrombotic risk, studies specifically investigating its impact on NETosis in autoimmune diseases are still needed. Ginger’s role as an adjuvant therapeutic intervention targeting a shared pathogenic mechanism (NETosis) in various autoimmune diseases offers an exciting avenue for future research and clinical trials.
This research paves the way for potential breakthroughs in the treatment of chronic autoimmune diseases and may hold promise for improving the lives of patients facing these challenging conditions.
In deep:
NETosis: A Common Mechanism of Autoimmunity and Thrombosis in APS and Lupus
Chronic, incurable autoimmune diseases such as antiphospholipid syndrome (APS) and lupus are associated with significant morbidity, mortality, and health care costs. These diseases have distinct clinical features, but share a common pathogenic mechanism: excessive neutrophil extracellular trap formation (NETosis). NETosis is a process by which neutrophils release their nuclear chromatin and granule proteins into the extracellular space, forming web-like structures that can trap and kill microbes. However, when NETosis is dysregulated, it can also cause tissue damage, inflammation, and thrombosis. In this article, we will review the evidence that links NETosis to the pathophysiology of APS and lupus, and discuss the potential therapeutic implications of targeting NETosis in these diseases.
NETosis and Autoantibody Formation
One of the hallmarks of APS and lupus is the presence of autoantibodies against various self-antigens, such as phospholipids, nuclear components, and neutrophil proteins. These autoantibodies can activate the complement system, bind to cell surface receptors, or form immune complexes that deposit in various organs, leading to tissue injury and organ dysfunction. The origin of these autoantibodies is not fully understood, but recent studies have suggested that NETosis plays a key role in breaking immune tolerance and inducing autoimmunity.
NETs can expose normally hidden self-antigens to the immune system, such as histones, DNA, RNA, and citrullinated proteins. These antigens can be taken up by antigen-presenting cells (APCs), such as dendritic cells or macrophages, and presented to T and B cells in the lymph nodes. NETs can also provide adjuvant signals that enhance the activation and differentiation of T and B cells into effector cells. For example, NETs can stimulate toll-like receptors (TLRs) on APCs and B cells, leading to the production of pro-inflammatory cytokines and chemokines. NETs can also activate the NLRP3 inflammasome in macrophages, resulting in the release of interleukin-1 beta (IL-1β) and IL-18. These cytokines can promote the survival and proliferation of autoreactive B cells and plasma cells.
Several animal models have demonstrated that NETosis can induce autoantibody formation and autoimmune disease. For instance, injecting mice with NETs or NET components can trigger the production of anti-nuclear antibodies (ANAs) and anti-phospholipid antibodies (aPLs), as well as glomerulonephritis and fetal loss. Conversely, blocking NETosis with deoxyribonuclease (DNase) or inhibitors of peptidylarginine deiminase 4 (PAD4), an enzyme involved in NET formation, can prevent or ameliorate autoimmunity in mice. Moreover, genetic or pharmacological ablation of neutrophils can also reduce autoantibody levels and disease severity in mouse models of lupus.
NETosis and Thrombosis
Another major complication of APS and lupus is thrombosis, which can affect both arterial and venous vessels of any size. Thrombosis is a multifactorial process that involves the interaction of blood cells, endothelial cells, coagulation factors, and inflammatory mediators. NETosis has been shown to contribute to thrombosis by several mechanisms. First, NETs can directly activate platelets and endothelial cells, leading to their adhesion and aggregation. Second, NETs can provide a scaffold for the assembly of coagulation factors and accelerate thrombin generation. Third, NETs can degrade natural anticoagulants, such as tissue factor pathway inhibitor (TFPI) and thrombomodulin ™, impairing the fibrinolytic system. Fourth, NETs can interact with complement components and aPLs, amplifying the inflammatory and prothrombotic responses.
Several animal models have demonstrated that NETosis can induce thrombosis and worsen its outcomes. For example, injecting mice with NETs or NET components can trigger arterial or venous thrombosis. Conversely, blocking NETosis with DNase or inhibitors of PAD4 or NADPH oxidase (NOX), an enzyme involved in NET formation, can prevent or reduce thrombus formation in mice. Moreover, genetic or pharmacological ablation of neutrophils can also protect mice from thrombosis.
NETosis and COVID-19
The coronavirus disease 2019 (COVID-19) pandemic has posed a major challenge for the management of APS and lupus patients, as they are at increased risk of severe infection and complications due to their underlying immunosuppression and comorbidities. COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can infect various cell types and trigger a hyperinflammatory response, known as the cytokine storm. COVID-19 patients can develop multiorgan abnormalities, such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), myocarditis, stroke, and coagulopathy. NETosis has been implicated in the pathogenesis of these complications, as NETs can damage the lung epithelium, impair gas exchange, activate the coagulation cascade, and induce vascular occlusion.
Several studies have reported elevated levels of NETs and NET markers in the plasma and bronchoalveolar lavage fluid of COVID-19 patients, especially those with severe disease or poor prognosis. Moreover, some studies have found an association between NETs and COVID-19-related biomarkers, such as D-dimer, ferritin, C-reactive protein (CRP), lactate dehydrogenase (LDH), and interleukin-6 (IL-6). Furthermore, some studies have shown that SARS-CoV-2 can directly induce NETosis in vitro by binding to angiotensin-converting enzyme 2 (ACE2) or TLR4 on neutrophils. Alternatively, SARS-CoV-2 can indirectly induce NETosis by stimulating other immune cells, such as monocytes or mast cells, to release NET-inducing factors, such as IL-1β or histamine.
Given the role of NETosis in COVID-19 complications, targeting NETosis may represent a potential therapeutic strategy for COVID-19 patients. Indeed, some studies have suggested that drugs that can modulate NETosis, such as dexamethasone, colchicine, hydroxychloroquine, or statins, may have beneficial effects on COVID-19 outcomes. However, more clinical trials are needed to confirm the efficacy and safety of these drugs in COVID-19 patients.
Conclusion
NETosis is a common mechanism of autoimmunity and thrombosis in APS and lupus. NETs can expose self-antigens to the immune system, induce autoantibody production, activate platelets and endothelial cells, promote coagulation and inflammation, and impair fibrinolysis. NETs can also contribute to the multiorgan abnormalities seen in COVID-19 patients. Targeting NETosis may offer a novel therapeutic approach for APS and lupus patients, as well as for COVID-19 patients. However, more research is needed to elucidate the molecular mechanisms of NETosis in these diseases and to identify the optimal targets and agents for NET inhibition.
References
: Erkan D., Aguiar C.L., Andrade D., Cohen H., Cuadrado M.J., Danowski A., Levy R.A., Ortel T.L., Rahman A., Salmon J.E., Tektonidou M.G., Willis R., Lockshin M.D. 14th International Congress on Antiphospholipid Antibodies Task Force report on antiphospholipid syndrome treatment trends. Autoimmun Rev. 2014;13:685–696.
: Knight J.S., Carmona-Rivera C., Kaplan M.J. Proteins derived from neutrophil extracellular traps may serve as self-antigens and mediate organ damage in autoimmune diseases. Front Immunol. 2012;3:380.
: Brinkmann V., Reichard U., Goosmann C., Fauler B., Uhlemann Y., Weiss D.S., Weinrauch Y., Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–1535.
: Fuchs T.A., Brill A., Wagner D.D. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol. 2012;32:1777–1783.
: Meroni P.L., Borghi M.O., Raschi E., Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011;7:330–339.
: Tsokos G.C. Systemic lupus erythematosus. N Engl J Med. 2011;365:2110–2121.
: Lood C., Blanco
reference link : https://insight.jci.org/articles/view/172011#SEC3
