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Journal Identification = MRH Article Identification = 0418 Date: April 6, 2017 Time: 1:32 pm

Magnesium Research 2017; 30 (1): 8-15 REVIEW

Burning , 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

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 sen- tinel 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 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 inflam- matory 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 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 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 , metabolic cycles, of the plasma levels of interleukin (IL)-6 and and signaling pathways [3]. Also Mg transpor- acute proteins, including complement com- ters are part of a large array of physiological and ponent C3 [11, 12]. These events correlate with an

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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 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 , 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 (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 and 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

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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 amines and [27]. Since Mg antagonizes Ca [17], Mg deficiency then lipid products. In the beginning, histamine raises cytosolic Ca, which facilitates degranula- locally released by mast cells induces a rapid vaso- tion by destabilizing membranes and activating dilation and augments endothelial permeability trimeric G proteins [28, 29]. It is interesting to producing intraendothelial gaps. As mentioned note that mice heterozygous for a TRPM7 kinase above, Mg deficiency facilitates the degranula- deletion are hypomagnesemic and hyperallergic tion of mast cells and, therefore, the release of [30], thus mimicking the phenotype of animals preformed mediators, among which histamine. that are fed a low-Mg diet. Therefore, the kinase Meanwhile, mast cells, endothelial cells, and other domain of TRPM7 assures proper Ca-induced cell types present in the site of inflammation begin exocytosis and regulates the Ca and Mg sensiti- to synthesize prostaglandins and prostacyclin, vity of G protein-coupled receptor-mediated mast vasodilators and vaso-permeabilizing agents, via cell degranulation by modifying granular mobi- cyclooxygenase. Also leukotrienes, which increase lity and/or histamine content. Also dendritic cells endothelial permeability, begin to be produced are present in tissues that are in contact with via lipoxygenase. Magnesium availability modu- the external environment where they sample the lates the synthesis of several of these mediators surrounding environment for pathogens [31]. If (figure 2). The biosynthesis of eicosanoids, mainly activated by the recognition of a pathogen, den- prostacyclin, is stimulated by Mg deficiency dritic cells engulf and process it, and migrate [36, 37]. Accordingly, magnesium suppresses the to the regional lymph nodes where they present activation of phospholipase A2 and the production

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Burning magnesium, a sparkle in acute inflammation: gleams from experimental models

PHOSPHOLIPIDS

phospholipase A2 Mg deficiency

ARACHIDONIC ACID

Mg deficiency cyclooxygenase lipoxygenase Mg deficiency

PROSTAGLANDINS I2/E2/D2 LEUKOTRIENS

Vasodilation vasopermeability

NO

NOS Mg deficiency

L-ARGININE

Figure 2. The modulation of the synthesis of eicosanoids by Mg deficiency.

of arachidonate metabolites in macrophages [38] Mg deficiency upregulates cell-surface adhesion and inhibits lipoxygenase activity in human leu- molecules, which renders the endothelium adhe- kocytes [39]. Moreover, Mg deficiency induces the sive for leukocytes [43], and the chemokines IL-8 production of platelet-activating factor, a vasodi- and monocyte chemoattractant protein-1 (MCP- lator, and vaso-permeabilizing factor [40] and the 1/CCL2) [42]. IL-8 attracts neutrophils, which synthesis of nitric , another potent inflamma- predominate in the inflammatory infiltrate during tory mediator that induces vascular permeability. the early phases, and stimulates their degra- In the plasma of Mg-deficient rats high concen- nulation with the consequent release of various tration of was found because of the that may contribute to tissue damage. activation of inducible oxide synthase [41]. MCP-1 is a potent chemotactic factor for many Endothelial cells are crucial in orchestrating the inflammatory cells including monocytes and T vascular reactions of acute inflammation. They cells, which accumulate in the late phases of secrete various molecules mediating vasodilata- inflammation. Also C-reactive protein (CRP), a tion and permeabilization such as prostacyclin modulator of innate immunity and a marker and nitric oxide, and release cytokines and of inflammation that increases in Mg deficiency chemokines that facilitate the recruitment of leu- [11, 44], exerts potent pro-inflammatory actions kocytes. In response to low extracellular Mg, on endothelial cells, i.e., by inducing the expres- cultured microvascular endothelial cells acti- sion of adhesion molecules [45]. It is likely that vate NF-kB, which induces the expression of a high levels of CRP cooperate with Mg deficiency large array of pro-inflammatory proteins [42]. to activate endothelial cells.

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Magnesium deficiency and acute Magnesium deficiency and acute inflammation: the cellular events inflammation: the resolution

Once attached to the endothelium, the leuko- When no longer needed, inflammation is acti- cytes transmigrate, pierce the basal membrane vely terminated to prevent unnecessary damage by secreting metalloproteases, and accumulate to tissues and restore their integrity and function. in extravascular sites. While no direct data are Resolution begins early through the coordinated available about the effects of Mg on leukocyte synthesis of various anti-inflammatory media- transmigration, it is reported that low Mg induces tors, among which IL-10, transforming growth the synthesis and the activity of metallopro- factor (TGF)␤, and pro-resolving lipid mediators teases [46], which facilitates the entry in the such as lipoxins, resolvins, and maresins [51]. inflamed tissues. After exiting the blood, leu- Even though little is known about the contri- kocytes migrate following the chemical gradient bution of Mg to this process, some evidence generated by locally produced chemoattractants, is available that supports that Mg deficiency among which leukotrienes, chemokines, and com- also has anti-inflammatory actions. By increa- ponents of the complement system. In the site of sing the synthesis of metalloproteases [46], which injury, leukocytes are functional for eliminating cleave chemokines, low Mg reduces the infiltra- the offending agents. In particular, the leuko- tion of leukocytes. Moreover, cells cultured in cytes capable of phagocytosis—neutrophils and low extracellular Mg produce high levels of IL-10 macrophages—are the principal players, since [47], which represses pro-inflammatory responses they ingest and destroy microbes, foreign sub- and limits unnecessary tissue disruptions. In stances, and necrotic tissues. The activation of microvascular endothelial cells, low extracellu- these cells is triggered by the elevation of intra- lar Mg rapidly activates NF-kB partly through cellular Ca with the consequent involvement of the overproduction of ROS, but later it also acti- phospholipase A2 and protein kinase C. Since vates peroxisome proliferator-activated receptor low extracellular Mg concentration leads to the (PPAR)␥ [42], probably through the induction increase of intracellular Ca and the activation of eicosanoids. PPAR␥ inhibits NF-kB by com- of protein kinase C [47], it is not surpri- plexing with NF-kB subunits and shuttling them sing that neutrophils and macrophages isolated from the nucleus to the cytoplasm [42]. We argue from Mg-deficient rats show higher phagocytosis that the activation of PPAR␥ in low Mg tips the than control animals [48]. However, extracellu- balance toward the resolution of inflammation lar Mg concentration has no significant impact (figure 3). Turning our attention to Mg transpor- on phagocytosis of cultured marrow-derived ters, it is noteworthy that TRPM7 channel activity antigen-presenting cells [32]. The discrepancy is implicated in macrophage polarization toward between ex vivo and in vitro results might be the anti-inflammatory M2 phenotype [52]. ascribed to the systemic response that accompa- nies Mg deficiency, namely the activation of the hypothalamo-pituitary adrenal cortex axis and the renin-angiotensin-aldosteron system, both contributing to alterations of the immune res- Conclusions ponse, as as the increased plasma levels of substance P and cytokines, which are important From the studies in vivo, ex vivo, and in priming agents [49]. Because killing of microbes vitro, it is clear that, under Mg deficiency, is accomplished by reactive oxygen species (ROS), pro-inflammatory events predominate over its it is noteworthy that phagocytes from Mg-deficient anti-inflammatory actions. Accordingly, physiolo- rats produce more ROS under basal conditions gic or high extracellular concentrations of Mg and are hyper-responsive to immune challenge exert anti-inflammatory properties. In cultured when compared with control animals [26, 48]. endothelial cells high Mg inhibits NF-kB and Remarkably, human neutrophils from healthy prevents the release of inflammatory mediators donors incubated in low Mg concentration sho- and cytokines [42], while in neutrophils and wed an increased respiratory burst in response macrophages Mg inhibits oxidative burst [53, 54]. to activating agents than controls in normal Mg Moreover, high extracellular Mg reduces the concentration [50]. release of inflammatory cytokines from leukocytes

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Burning magnesium, a sparkle in acute inflammation: gleams from experimental models

MgMg deficiency deficiency ROS EICOSANOIDS IL-10

ACTIVATION OF NF-κB ACTIVATION OF PPARγ

pro-inflammatory anti-inflammatory environment environment

Figure 3. A summary of pro- and anti-inflammatory actions of Mg deficiency.

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