Magnesium and inflammation: Advances and perspectives
Graphical Abstract
Introduction
The first report describing the use of magnesium (Mg) to control inflammation dates back to a century ago, when the successful treatment of panophthalmitis was described and attributed to the generation of a hyperosmolar environment which was detrimental to microorganisms [1]. It is only in the Eighties that experimental studies in vitro and in vivo as well as epidemiological surveys establish a connection between low Mg status and inflammation and begin to unveil the cellular and molecular mechanisms involved. This association is not surprising, considering that Mg, the fourth most abundant cation in the human body, is essential to maintain the homeostasis of all our cells and tissues, since it models cell proliferation and death and shapes metabolism [2] (Fig. 1). Mg is also required to forge the immune system. Interestingly, Mg deficiency impairs the response of the adaptive immune cells, while it activates the innate immune system and promotes inflammation [2].
In spite of Mg undisputedly critical functions, subclinical Mg deficiency is rather common because of insufficient Mg intake, medications, chronic diseases, and has been numbered as a possible public health concern for adults [3].
In this review, we initially summarize how Mg deficiency promotes some typical signs of acute inflammation and enhances inflammatory response. In light of this, we speculate about the potential contribution of a low Mg status to some pathogenic aspects of COVID-19. We then discuss the association between Mg deficiency and chronic inflammation, which is the common thread in many non-communicable diseases, the leading causes of morbidity, disability and mortality. Because the discovery of Mg transporters has raised a significant resurgence of interest in Mg research, we will provide a concise overview of present knowledge about their role in inflammation.
Section snippets
Mg deficiency, acute inflammation and enhanced inflammatory response with a glance to COVID-19
Major advances in supporting the association between Mg deficiency and inflammation stem from experimental studies in vivo and in vitro. In rodents the drop of magnesemia leads to the typical signs of an acute inflammatory response, i.e. hyperemia, edema, rise of acute phase proteins and circulating pro-inflammatory cytokines, such as interleukin (IL)1, IL6 and Tumor Necrosis Factor (TNF)α [4]. Moreover, substance P, a tachykinin present in the central and peripheral nervous systems and also
Mg deficiency and chronic inflammation: a role in non-communicable diseases
Several studies demonstrate that a moderate or subclinical Mg deficiency induces a low grade, chronic smoldering inflammation, which is a powerful risk factor for frailty and the common denominator of many common pathological conditions among which cardiovascular diseases, diabetes, asthma, preeclampsia, osteoporosis, inflammatory bowel diseases, mental health disorders and neurodegenerative diseases [2]. Biomarker of chronic inflammation is a modest 2–4 fold increase of inflammatory mediators,
An overview on the potential mechanisms implicated in low Mg-induced inflammation
Several mechanisms can be envisioned to explain how low Mg promotes inflammation. Since Mg is involved in the regulation of all metabolic pathways and in redox balance, its deficiency generates a metabolic and energetic stress and is associated with the accumulation of free radicals. All these events force the cells to activate an adaptive response, with consequent altered functions. This happens in endothelial cells in vitro, which produce high amounts of reactive oxygen species when cultured
Mg transporters and inflammation
Since Mg functions as a second messenger [82], it is noteworthy that several channels and transporters that promote Mg transients have been characterized as well as transporters that extrude Mg to the extracellular space or drive it into organelles to store it.
The ubiquitously expressed ion channel transient receptor potential melastatin (TRPM)7 has the functional duality of being an ion channel, mainly permeable to Ca and Mg cations, and a kinase [83]. The involvement of TRPM7 in inflammation
Conclusions and perspectives
Inflammation, regarded as a protective response to tissue damage, is finely tuned with a swift initiation and a timely resolution [100]. When uncontrolled or unresolved, inflammation is harmful and leads to diseases. In the past twenty years, a large amount of data established that Mg deficiency contributes both to hyperinflammation in acute inflammatory processes and to low grade inflammation in chronic diseases. While the cellular and molecular mechanisms have been in part disclosed, there
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors declare no conflict of interest. All the authors contributed to writing and proof reading the article.
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