Burning Magnesium, a Sparkle in Acute Inflammation: Gleams from Experimental Models

Journal Identification = MRH Article Identification = 0418 Date: April 6, 2017 Time: 1:32 pm Magnesium Research 2017; 30 (1): 8-15 REVIEW Burning magnesium, a sparkle in acute inflammation: gleams from experimental models Sara Castiglioni, Alessandra Cazzaniga, Laura Locatelli, Jeanette AM Maier Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Milano, I-20157, Italy Correspondence: Dipartimento di Scienze Biomediche e Cliniche Luigi Sacco, Università di Milano, Via GB Grassi, 74 Milano 20157, Italy <[email protected]> Abstract. Magnesium contributes to the regulation of inflammatory responses. Here, we focus on the role of magnesium in acute inflammation. Although present knowledge is incomplete to delineate an accurate scenario and a sche- dule of the events occurring under magnesium deficiency, it emerges that low magnesium status favors the induction of acute inflammation by sensitizing sentinel cells to the noxious agent, and then by participating to the orchestration of the vascular and cellular events that characterize the process. Key words: magnesium, acute inflammation, leukocytes, endothelial cells Inflammation has been observed since the pathological processes, including the regulation of beginning of documented medical knowledge [1], immune response [3-7]. TRPM7, which possesses but the disclosure of its significance and com- an ion transport domain and an active kinase plexity is rather recent. It is now clear that domain and is responsible for cellular Mg homeo- inflammation is the automatic response of living stasis, phosphorylates phospholipase C␥2, crucial tissues to damage. Through a series of inter- in intracellular signaling after the activation of connected events involving blood vessels and B lymphocytes, and is implicated in T cell migra- leukocytes, it defends from damages and paves the tion [7, 8]. MAGT1, a highly selective transporter way for the repair of injured tissues and organs. for Mg, has a key role in T cell-mediated immune Inflammation is activated by the release of che- responses [9]. mical mediators that induce vascular and cellular events with the objective of recruiting inflammatory cells, and in particular, innate immune cells such as neutrophils and macrophages. These Magnesium deficiency cells, in turn, phagocytize the noxious agent and and acute inflammation produce additional chemical mediators that even- tually lead to the activation of the adaptive Mg deficiency impairs adaptive immune response, immune response. while it induces inflammation in vivo and in vitro A link between inflammation and magnesium [10]. In rodents, a severely Mg-restricted diet doi:10.1684/mrh.2017.0418 deficiency has been established long ago [2]. rapidly results in a dramatic drop of magnese- Magnesium (Mg) is an essential cation, which mia which leads to characteristic inflammatory maintains vital cellular functions, since it is invol- responses, such as hyperemia and edema, accom- ved in all major cellular processes, including the panied by leukocytosis and a significant increase regulation of energy metabolism, metabolic cycles, of the plasma levels of interleukin (IL)-6 and and signaling pathways [3]. Also Mg transpor- acute phase proteins, including complement com- ters are part of a large array of physiological and ponent C3 [11, 12]. These events correlate with an 8 Pour citer cet article : Castiglioni S, Cazzaniga A, Locatelli L, Maier JA. Burning magnesium, a sparkle in acute inflammation: gleams from experimental models. Magnes Res 2017 ; 30(1) : 8-15 doi:10.1684/mrh.2017.0418 Journal Identification = MRH Article Identification = 0418 Date: April 6, 2017 Time: 1:32 pm Burning magnesium, a sparkle in acute inflammation: gleams from experimental models Mg deficiency ROS SYNTHESIS NO SYNTHESIS IMBALANCE Ca/Mg ALTERED RELATIONSHIP NEUROGENIC HOST/GUT MICROBIOTA INFLAMMATION PEROXYNITRITE inflammation Figure 1. Possible mechanisms implicated in low-Mg-related inflammation. impaired redox capacity characterized by a sub- bifidobacteria in the intestine, an impairment of stantial increase in thiobarbituric acid-reactive gut barrier and high levels of tumor necrosis factor substances associated with a significant reduc- (TNF)␣ and IL-6 mRNA in the liver and intestine. tion of the activity of superoxide dismutase and After 21 days of such a dietetic regimen, the bifi- catalase [13]. Moreover, Mg deficiency reduces the dobacteria content increases, the performance of synthesis of antioxidant glutathione, a reaction the intestinal barrier is restored, and inflamma- that is Mg dependent [14]. Short-term Mg defi- tion declines [21]. These findings suggest that a ciency induces also de novo synthesis of ceramide, dynamic adaptive response occurs in animals that which activates nuclear factor kappa-light-chain- are fed a Mg-poor diet. enhancer of activated B cells (NF-kB), the master On these bases, several mechanisms seem to be regulator of inflammation, and induces the release involved in Mg deficiency induction of inflamma- of some inflammatory cytokines and chemokines tion: i) an altered symbiotic relationship of the [15]. host with the gut microbiota; ii) oxidative stress Experimentally induced hypomagnesemia is generated by the excessive production of free associated with altered calcium (Ca) homeosta- radicals; iii) the activation of neurogenic inflam- sis [16]. For this purpose, it is noteworthy that mation; and iv) a Ca/Mg imbalance (figure 1). Mg is considered the natural Ca antagonist [17] On the other hand, under stressful condi- and, accordingly, Ca deficiency attenuates the tions, and inflammation certainly is a stress pro-inflammatory effects of dietary Mg restric- [22], the concentrations of magnesium decrease tion [16, 18]. Moreover, circulating substance [23]. Recently, a reduction in Mg has been des- P, a pro-inflammatory neuropeptide, increases cribed in acutely inflamed tissues and this is early in experimental dietary Mg deficiency. Sub- caused by the activation of the IL-33/ST2 axis stance P and other mediators contribute to the [24]. These results suggest that a decrease in production of reactive oxygen and nitrogen spe- Mg concentrations in the inflammatory site is cies, which ultimately promote inflammation [19]. secondary to inflammation itself and might contri- Since a link exists between inflammation and the bute to the exacerbation of inflammatory response composition of the microbiota, which educates the to immune challenge in Mg-deficient animals. immune system [20], it is noteworthy that a Mg- Indeed, a poor-Mg diet increases the vulnera- deficient diet is associated with a lower content of bility to lipopolysaccharide (LPS) in vivo and 9 Journal Identification = MRH Article Identification = 0418 Date: April 6, 2017 Time: 1:32 pm S. CASTIGLIONI, ET AL. enhances the response of neutrophils and macro- the antigen to T lymphocytes, thereby shaping phages ex vivo [25]. That Mg is directly implicated immune response. Mg deficiency does not signi- in this hypersensitivity to LPS is demonstra- ficantly impact dendritic cell function in a model ted by the prevention of these effects with Mg of coculture with lymphocytes [32]. However, it supplementation. In Mg-deficient animals the is known that high extracellular Mg significantly addition of magnesium before endotoxin signi- suppresses the antigen-presenting capacity of the ficantly increases survival and lowers plasma Langerhans cells, because it reduces the expres- values of TNF␣ [26]. sion of HLA-DR and costimulatory B7 molecules We will here summarize the involvement of Mg by the dendritic cells [33]. To our knowledge, no deficiency in the principal steps of acute inflam- data are available about Mg and its transporters mation, i.e., the recognition of the noxious agent, on the function of fibroblasts. Since injury and the delivery of leukocytes to the damaged tissue to mechanical stress induce the release from fibro- eliminate it, and the termination of the process. blasts of biologically active IL-33 [34], which acts as an alarmin, it would be interesting to evaluate whether Mg deficiency modulates IL-33 release in these cells. In general, studies on the effects Magnesium deficiency and acute of low Mg on fibroblasts should be fostered, since inflammation: sensing the damage these cells respond to tissue injury by conditioning the production of cytokines and the recruitment of If inflammation is due to external pathogens inva- leukocytes in areas of inflammation [35]. ding a tissue, two sets of signals trigger the whole process. The first one sparks from the patho- gen itself; the second one originates from the cells that have been damaged. In the case of Magnesium deficiency and acute sterile inflammation, the signals that alert the inflammation: the vascular events organism are endogenous and derive from the injured cells. Sentinel cells in the tissues, i.e., Important vascular events characterize the early mast cells, dendritic cells, and fibroblasts, per- phases of acute inflammation. Vasodilation leads ceive the offending agent and then alert neighbor to an increase of blood flow and is quickly follo- cells, thus initiating inflammation. Mast cells are wed by the raise of capillary permeability, with very abundant in the skin and in the muco- the aim of boosting the accumulation of plasma sal tissues where they represent a first line of proteins in the site of damage. These events defense against external insults. In rats, Mg defi- are driven by the interconnected action of seve- ciency increases the degranulation of mast cells ral mediators, initially vasoactive

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