Immune regulation , cell signalling and magnesium sensing
CD8 + T-cells are a key component of the adaptive immune system , playing a critical role in recognising and eliminating infected or malignantly transformed cells . Magnesium is a critical catalyser of the CD8 + T-cell and its potency . It does this by interfacing with the cell surface Lymphocyte function-associated antigen ( LFA-1 ), which is a protein that plays a critical role in T-cell activation and signal transduction . It is a type of transmembrane receptor responsible for communication between the cell and the extracellular matrix ( ECM ).
LFA-1 is involved in T-cell activation , immune synapse formation , leukocyte trafficking , and the movement of T-cells from blood vessels into the surrounding tissue ( extravasation ). In the process of T-cell activation , LFA-1 acts as a docking site for target cells .
“ In the inactive state this docking site is in a bent conformation and cannot efficiently bind to infected or abnormal cells . This is where magnesium comes into play . If magnesium is present in sufficient quantities in the vicinity of the T-cells , it binds to LFA-1 and ensures that it remains in an extended and active conformation .” 2
The MAGT1 transporter protein moves charged ions of magnesium into T and B cells , which is essential to prevent cytotoxicity and to support mitochondrial metabolism . “ In T-cells and B cells , MAGT1 deficiency lowered cytosolic free magnesium and hindered magnesium absorption .“ 3
As magnesium is essential for production of enzymes , a magnesium deficiency can lead to a deficiency in the MAGT1 magnesium transporter , which can then further restrict magnesium access to mitochondria , resulting in a negative feedback loop .
Chronic inflammation from magnesium deficiency is linked to the production and release of “ interleukin-1 ( IL-1 ), tumour necrosis factor ( TNF ), as well as the activation of phagocytosis , calcium channel opening , NMDA receptor activation , NF-B signalling , and stimulation of nitric oxide with inflammatory markers .” 3 Further , “ Studies have shown that Mg deficiency can promote platelet agglomeration , which can affect micro-vascular functions , and limit the growth and migration of endothelial cells . Additionally , research suggests that the stimulation of the IL-33 / ST2 axis , a key pathway in inflammation , can lead to decreased Mg levels in severely inflamed tissues .” 3
Oxidative stress and mitochondria
If magnesium levels drop too low in cells , redox balance is compromised and mitochondrial function is inhibited in order to protect them from oxidative stress , the ravages of Reactive Oxygen Species ( ROS ) and lowering of pH to the acidic range . When magnesium is deficient and pH is too low , the entry of glucose and insulin via the cell membrane is restricted to some extent in order to lessen mitochondrial respiration , so that fewer ROS waste products are produced in order to mitigate excessive oxidative stress .
Normally , ROS must be rapidly neutralised and cleared away so that free radicals don ’ t get a chance to steal electrons from cell organelles and mitochondria , causing injury . Seen in this light , insulin resistance becomes cell protective , but of course has other tradeoff side effects .
Magnesium supplementation improves mitochondrial function through various mechanisms , such as mitochondrial ROS inhibition , modulation of membrane permeability , transition channel opening and calcium antagonism . Magnesium is protective of mitochondria , as confirmed in this study by Fujita et al .: “ Our results suggest that Mg2 + that has dissociated from ATP is not merely a byproduct , but functions as a cytoprotective mechanism against oxidative stress and that Mg2 + supplementation is effective in protection against oxidative stress .” 4
Magnesium deficiency is associated with lipid peroxidation , cytotoxicity , lowering of hepatic glutathione and vitamin E levels , as well as superoxide dismutase ( a vital mitochondrial antioxidant ), which further leads to an increase in oxidative stress . Magnesium not only works synergistically with other antioxidants , but by itself also donates electrons , thereby working as an antioxidant to scavenge free oxygen radicals .
Problems with neutralisation and clearance of ROS metabolic wastes leads to oxidative stress and age-associated mitochondrial dysfunction , expressed as systemic inflammation . Autoimmune conditions can develop in the presence of “ self-garbage ( mtDNA , cardiolipin , or formyl peptides ) that may be detected by macrophages . Mg insufficiency disrupts the electron transport chain and facilitates the generation of reactive oxygen species ( ROS ). The reduced protein expression of manganese superoxide dismutase , including catalase , is indeed driven by magnesium deprivation , affecting the antioxidant defensive reaction . Mg deprivation reduces ATP biosynthesis via down-regulating ATP synthase ( F0F1 ). Intracellular Mg insufficiency prohibits Mg from accessing mitochondria via the mitochondrial RNA splicing 2 ( MRS2 ) protein and triggers Mg efflux .” 3
When excessive magnesium is lost from cells , it causes membrane channel dysfunction and subsequent loss of potassium and hydration from cells , which lowers pH and slows cell respiration .
Endothelial dysfunction in auto-immune disorders : Crohn ’ s disease , colitis , psoriasis , respiratory disorders , and slow healing leg ulcers
Endothelial dysfunction associated with the development of an inflammatory syndrome is accompanied by the activation of leukocytes and macrophages . Levels of proinflammatory
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