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Writer's pictureDavid Ojcius

Magnesium-enriched deep-sea water inhibits NLRP3 inflammasome activation and dampens inflammation

The NLRP3 inflammasome is an essential component of the innate immune system, but excessive activation can lead to inflammatory diseases. Ion fluxes across the plasma membrane or from intracellular stores are known to regulate NLRP3 inflammasome activation. Deep-sea water (DSW) contains high concentrations of many mineral ions, which could potentially influence NLRP3 inflammasome activation. However, the impact of DSW on NLRP3 inflammasome activation has not been investigated. Here, we demonstrated that DSW with water hardness levels up to 500 mg/L did not affect cell viability or the expression of NLRP3 inflammasome components in macrophages derived from THP-1 cells. However, the DSW significantly inhibited IL-1β secretion and caspase-1 activation in response to NLRP3 activators such as nigericin, ATP, or monosodium urate (MSU) crystals. Mechanically, it was discovered that the presence of 5 mM magnesium ions (Mg2+), equivalent to the Mg2+ concentration found in the DSW with a water hardness of 500 mg/L, inhibits NLRP3 inflammasome activation. This indicates that Mg2+ contributes to the mechanism by which DSW mitigates NLRP3 inflammasome activation. Moreover, DSW administration effectively lessens MSU-triggered peritonitis in mice, a commonly used model for examining the impacts of NLRP3 inflammasome activation. These results show that DSW enriched with Mg2+ could potentially be beneficial in modulating NLRP3 inflammasome-associated diseases.


NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a complex of proteins found in the cytoplasm, activated by disturbances from infections or non-infectious injuries [1]. When activated, NLRP3 begins to form oligomers and attracts the protein apoptosis-associated speck-like protein containing a CARD (ASC), which in turn activates caspase-1. This enzyme is crucial for converting pro-interleukin 1 beta (pro-IL-1β) into IL-1β, an important proinflammatory cytokines [2]. Growing research shows that uncontrolled NLRP3 inflammasome activation is linked to the development of multiple inflammatory conditions, including gout, diabetes, atherosclerosis, and Muckle-Wells syndrome [3]. In the case of gout, NLRP3 inflammasome activation in macrophages is specifically caused by the presence of monosodium urate (MSU) crystals [4,5].

NLRP3 inflammasome activation involves a two-step process requiring both priming and activation signals [1]. First, a priming signal is necessary to prepare the macrophages for activation. This priming step is triggered by various factors which activate NF-κB. As a result, expression of NLRP3 and pro-IL-1β increases. Following priming, NLRP3, which is a pattern recognition receptor, can be activated by a wide range of bacterial pore-forming toxins (e.g., nigericin), endogenous danger molecules (e.g., ATP) [6], and crystal molecules (e.g., MSU) [7], which leads to assembly of the NLRP3 inflammasome. Despite the chemical and structural diversity of these activating stimuli, they all seem to trigger a common cellular signal that NLRP3 can sense. These signals include ion flux, mitochondrial dysfunction, lysosomal disruption, trans-Golgi disassembly and metabolic alterations [2]. Notably, emerging evidence suggests that changes in the intracellular concentrations of different ions, such as potassium (K+), sodium (Na+), calcium (Ca2+), magnesium (Mg2+), manganese, zinc, iron, and chloride, may modulate NLRP3 activation by various activators [8]. The permeation of the plasma cell membrane to K+ and Na+ is a common response induced by many NLRP3 agonists [9]. A reduction in intracellular K+ concentration is sufficient to activate the NLRP3 inflammasome, while an increase in intracellular Na+ is not strictly necessary for inflammasome activation. Consequently, potassium efflux enhances NLRP3 inflammasome activation by promoting the interaction between NLRP3 and NEK7 [10]. Specifically, an increase in cytoplasmic Ca2+ levels plays a crucial role in NLRP3 inflammasome activation triggered by various stimuli [11,12]. Ca2+ can originate from different sources, including the endoplasmic reticulum, lysosomal lumen, and the extracellular environment [8]. Interestingly, extracellular Mg2+ antagonizes the role of Ca2+ in NLRP3 inflammasome activation by inhibiting Ca2+ influx [12,13].

Deep-sea water (DSW) is defined as ocean water from a depth of over 200 meters [14]. Salient features of DSW include its high inorganic nutrient salt concentration, clarity, enriched trace elements, and stability [15]. Previous research indicates that using DSW as a treatment can be effective in addressing health issues commonly linked to lifestyle diseases, including diabetes, obesity, cardiovascular disease, cancer, and dermatological conditions [16]. DSW treatment could facilitate a decrease in the incidence of cardiovascular disease [15,17], inhibit the progression of atherosclerosis [18], improve glucose tolerance and regulate function of glucagon and insulin [19,20], inhibit adipocyte differentiation [21,22,23], inhibit the metastatic potential of malignant cells [24], and protect the mice from 2,4-dinitro-chlorobezene-induced atopic dermatitis-like skin lesions [25]. In addition, DSW promotes osteoporosis recovery through bone regeneration [26] and accelerates recovery from physical fatigue [2]. Although DSW is known to provide potential health benefits, more evidence is still needed to understand the mechanisms whereby DSW regulates physiological functions.

Using macrophage cell culture in vitro as well as a mouse peritonitis model in vivo, we propose that DSW treatment has beneficial effects by modulating NLRP3 inflammasome-associated diseases. We shows that DSW with a water hardness of 500 mg/L can inhibit NLRP3 inflammasome activation in response to various stimuli, and that Mg2+ plays an active role in the effects of DSW by inhibiting NLRP3 inflammasome activation. Finally, we show that treating mice with DSW, which is enriched in Mg2+, lessens MSU-induced peritonitis—a model frequently used to explore the effects of NLRP3 inflammasome activation in vivo. These results enhance our knowledge of magnesium's influence on NLRP3 inflammasome activation and imply that DSW with high magnesium content may mitigate diseases associated with this inflammasome.



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