The Versatile Role of Nicotinamide Adenine Dinucleotide in Immunity

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Background

Nucleotides play a key role in innate and adaptive immune responses. They are an essential intracellular energy currency and serve as important signaling molecules. Once released into the extracellular space, they can act as danger-associated molecular patterns (DAMPs) to alert the immune system. Adenosine triphosphate (ATP), as the main energy currency, is present at millimolar concentrations in practically every metabolically active cell, from which it can be released upon cellular stress and damage. Thereby, it can serve as a perfect indicator of tissue damage when present in the extracellular milieu. In innate immune cells, ATP is a strong trigger of NLRP3-inflammasome formation and IL-1β release. On the adaptive immunity side, extracellular ATP can have different roles depending on its concentration. Low level of ATP released upon T cell activation, can serve as an autocrine stimulus linked to a tonic activation of P2X1, P2X4 or P2X7. This is perceived as an enhancing stimulus to boost IL-2 production, T cell migration or metabolic fitness. In contrast, high extracellular levels of ATP in the vicinity of damaged tissues can trigger T cell death.

Interestingly much less is known about nicotinamide adenine dinucleotide (NAD), another highly abundant intracellular molecule used as energy currency. Intracellularly, NAD and its metabolic products ADP-ribose (ADPR), 2’-deoxy-ADPR (from 2’deoxy-NAD), cyclic ADPR (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are important second messengers essential for leukocyte Ca2+ signaling. Metabolism of these signaling molecules, as well as their exact molecular targets, are still unknown in many aspects, despite their importance for central processes of adaptive immunity, e.g. T cell activation. Further, there are only a few cell surface receptors identified, such as P2Y1 and P2Y11 that can sense extracellular NAD. Of note, the extracellular signaling capacity of NAD is broadened by various nucleotide-degrading cell surface (ecto-) enzymes that can generate a variety of other nucleotide metabolites: ecto-CD38 metabolizes NAD into ADPR and cADPR, ecto-nucleotide pyrophosphatases (ENPPs) such as ENPP1 generate adenosine monophosphate (AMP) directly from NAD or from ADPR, thereby providing substrate for CD73-catalyzed adenosine generation and ligands for P1 receptors. Ecto-ADP-ribosyltransferases (ARTCs) utilize extracellular NAD to covalently attach ADPR groups to arginine residues of multiple different cell surface proteins, including P2X7, resulting in a post-translational modification that can significantly affect the function of the modified target. In summary, NAD and its metabolites inside and outside of cells can have a remarkable impact on many different regulatory pathways of immunity.

The goal of this Research Topic is to collect high-quality Review and Original Research articles that focus on the role and function of intracellular and extracellular NAD and NAD-derived metabolites as modulators of immunity. We welcome submissions that cover the following topics:

- Receptors on immune cells that can sense extracellular NAD.
- Intracellular signaling by NAD derivatives/metabolic products in immune cells
- NAD-utilizing ecto-enzymes and the impact of their catalytic products on immune cell functions
- Mechanisms of NAD release during an immune response
- Pharmacological manipulation of receptors/enzymes involved in NAD signaling in immunity

Keywords: nicotinamide adenin dinucleotide, NAD, cADPR, purinergic signalling, ecto-nucleotidases

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