Recent research has demonstrated that the amount of NAD+ present in the body directly correlates with the efficiency of natural killer cells, an essential component of the immune system. Natural killer (NK) cells are essential to the innate immune system. This makes them one “initial responders” to primarily viral infections and malignancies in their early stages. To recruit additional immune cells to battle, NK cells secrete cytokines and chemokines.
The ability of natural killer (NK) cells to eliminate pathogenic cells is one facet of immunity that naturally calls for backup declines with age. The drop in vaccination and anti-tumour response with age has been connected to immunosenescence. Nonetheless, its internal workings have not been fully evaluated.
NAD+ Being an Energy Provider for Natural Killer Cells.
Cellular battle demands a significant amount of energy. It is well known that activated NK cells boost their mitochondrial energy production, which strongly relies on the coenzyme NAD+. NAD+, a ubiquitous molecule that also aids in other vital functions, diminishes significantly with age, perhaps contributing to numerous age-related deficits.
In this recent study, the researchers postulated that NAD+ is associated with the lethal potential of NK. They determined that NK activation by the pro-inflammatory cytokines IL-12 and IL-15 led to a rise in NAD+ and the expression of enzymes involved in NAD+ synthesis. The addition of NAD+ to NK cells increased the synthesis of many NK cellular weapons, such as perforins. The treated NK cells have shown increased cytotoxicity, proliferative potential, and viability.
There are three methods in which cells generate NAD+, and the researchers determined that the upregulation of NAD+ synthesis in activated NK cells is driven mostly by the salvage route. Niacinamide (vitamin B3) is produced from NAD+ when NAD+ is used in the cell. Utilizing the NAD+ precursors’ nicotinamide riboside (NR) and nicotinamide mononucleotide, NAM is converted back to NAD+ through salvage. Key role played by the enzyme NAMPT in this process. The researchers observed that inhibiting NAMPT had the opposite effect of inhibiting NMN, which had the same favourable effects as NAD+.
Turning the Tumor Game.
Immune cells, including NK cells, have their cytotoxic and cytokine-producing capabilities diminished by the tumour microenvironment. The scientists speculated that NAD+ might also be involved. They analyzed the transcriptomes of murine tumour-derived NK cells to identify significantly downregulated genes due to NAD+ depletion. NK cells exposed to cancer cell medium had their NAD+ levels and NAMPT expression lowered.
By analysing NAMPT expression in NK cells using 50 human hepatocellular carcinomas (HCC) samples, the researchers discovered a favourable correlation between NAMPT expression and patient survival. Supplementation with NMN increased the anti-tumour activity of NK cells, while knocking down NAMPT in a mouse model of HCC dramatically sped up tumour development and lowered survival. Researchers inserted melanoma cells and either NMN-treated or control NK cells into a mouse model of the disease and discovered that the treated cells significantly suppressed tumour development.
Additionally, the authors discovered a possible reason for the decreased effectiveness of NK cells in tumours. Lactate, also known as the lactic acid conjugate base, is in high concentrations. Experiments indicated that reducing lactate absorption had the opposite effect on NAMPT expression compared to treating NK cells with lactate, suggesting a dose-dependent link between the two.