Extracellular NAD+ inhibits human neutrophil apoptosis

Pliyev, Boris K.; Ivanova, Anna; Vg, Savchenko

doi:10.1007/s10495-013-0948-x

Cited by 18 publications

(10 citation statements)

References 51 publications

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“…We investigated if signaling of β-NAD is mediated via purinergic P2Y1 and/or P2Y11 receptors, as reported previously by several authors for diverse cell types [ 20 , 21 , 25 , 52 , 53 , 54 ]. P2Y1 and P2Y11 receptors are membrane receptors of ATP and β-NAD that, depending on their interacting G proteins, induce diverse signaling cascades.…”

Section: Discussionmentioning

confidence: 99%

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β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells

Hiller

Heldmann

Richter

et al. 2018

IJMS

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While interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine essential for host defense, high systemic levels cause life-threatening inflammatory syndromes. ATP, a stimulus of IL-1β maturation, is released from damaged cells along with β-nicotinamide adenine dinucleotide (β-NAD). Here, we tested the hypothesis that β-NAD controls ATP-signaling and, hence, IL-1β release. Lipopolysaccharide-primed monocytic U937 cells and primary human mononuclear leukocytes were stimulated with 2′(3′)-O-(4-benzoyl-benzoyl)ATP trieethylammonium salt (BzATP), a P2X7 receptor agonist, in the presence or absence of β-NAD. IL-1β was measured in cell culture supernatants. The roles of P2Y receptors, nicotinic acetylcholine receptors (nAChRs), and Ca2+-independent phospholipase A2 (iPLA2β, PLA2G6) were investigated using specific inhibitors and gene-silencing. Exogenous β-NAD signaled via P2Y receptors and dose-dependently (IC50 = 15 µM) suppressed the BzATP-induced IL-1β release. Signaling involved iPLA2β, release of a soluble mediator, and nAChR subunit α9. Patch-clamp experiments revealed that β-NAD inhibited BzATP-induced ion currents. In conclusion, we describe a novel triple membrane-passing signaling cascade triggered by extracellular β-NAD that suppresses ATP-induced release of IL-1β by monocytic cells. This cascade links activation of P2Y receptors to non-canonical metabotropic functions of nAChRs that inhibit P2X7 receptor function. The biomedical relevance of this mechanism might be the control of trauma-associated systemic inflammation.

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Section: Discussionmentioning

confidence: 99%

“…β-NAD also acts as an extracellular signaling molecule regulating immunity [ 16 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Extracellular β-NAD levels, similar to extracellular ATP levels, are low under steady-state conditions but rise, whenever cells are damaged and cytoplasm is released [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells

Hiller

Heldmann

Richter

et al. 2018

IJMS

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“…Nicotinamide adenine dinucleotide (NAD + ) is also capable of activating P2Y 11 and causing an increase in intracellular Ca 2+ , IP 3 , and cAMP in P2Y 11 transfected 1321N1 cells [58,59]. Human mesenchymal stem cells and neutrophils are activated by NAD + presumably through P2Y 11 [60,61]. In these studies, specificity of the response was determined by inhibiting NAD + -signalling with G s and protein kinase A (PKA) inhibitor, NF157 antagonist, and P2RY11 knockdown.…”

Section: +mentioning

confidence: 99%

A critical look at the function of the P2Y11 receptor

Dreisig

Kornum

2016

Purinergic Signalling

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The P2Y 11 receptor is a member of the purinergic receptor family. It has been overlooked, somewhat due to the lack of a P2ry11 gene orthologue in the murine genome, which prevents the generation of knockout mice, which have been so helpful for defining the roles of other P2Y receptors. Furthermore, some of the studies reported to date have methodological shortcomings, making it difficult to determine the function of P2Y 11 with certainty. In this review, we discuss the lack of a murine BP2Y 11 -like receptor^and highlight the limitations of the currently available methods used to investigate the P2Y 11 receptor. These methods include protein recognition with antibodies that show very little specificity, gene expression studies that completely overlook the existence of a fusion transcript between the adjacent PPAN gene and P2RY11, and agonists/antagonists reported to be specific for the P2Y 11 receptor but which have not been tested for activity on numerous other adenosine 5′-triphosphate (ATP)-binding receptors. We suggest a set of criteria for evaluating whether a dataset describes effects mediated by the P2Y 11 receptor. Following these criteria, we conclude that the current evidence suggests a role for P2Y 11 in immune activation with cell typespecific effects.

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“…7,8,20 The roles of PKA in neutrophil lifespan have also been described, and PKA activation has been shown to have both prosurvival and proapoptotic outcomes. [21][22][23] In contrast to the prosurvival roles of PKA in vitro, PKA was found to play a role in the resolution of neutrophilic inflammation in vivo by driving neutrophil apoptosis. 23 In our study, activation of PKA by N6/8-AHA, a selective PKA type 1 agonist, results in a profound transcriptional response and upregulated more genes in neutrophils than any other proinflammatory stimulus tested.…”

Section: Discussionmentioning

confidence: 95%

NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival

Prince

Prosseda

Higgins

et al. 2017

Blood

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Key Points• We demonstrate an important role for NR4A receptors in regulating neutrophil lifespan and homeostasis in vitro and in vivo.• These findings may define targets for therapies for diseases driven by defects in neutrophil number and/or survival.The lifespan of neutrophils is plastic and highly responsive to factors that regulate cellular survival. Defects in neutrophil number and survival are common to both hematologic disorders and chronic inflammatory diseases. At sites of inflammation, neutrophils respond to multiple signals that activate protein kinase A (PKA) signaling, which positively regulates neutrophil survival. The aim of this study was to define transcriptional responses to PKA activation and to delineate the roles of these factors in neutrophil function and survival. In human neutrophil gene array studies, we show that PKA activation upregulates a significant number of apoptosis-related genes, the most highly regulated of these being NR4A2 and NR4A3. Direct PKA activation by the siteselective PKA agonist pair N6/8-AHA (8-AHA-cAMP and N6-MB-cAMP) and treatment with endogenous activators of PKA, including adenosine and prostaglandin E2, results in a profound delay of neutrophil apoptosis and concomitant upregulation of NR4A2/3 in a PKA-dependent manner. NR4A3 expression is also increased at sites of neutrophilic inflammation in a human model of intradermal inflammation. PKA activation also promotes survival of murine neutrophil progenitor cells, and small interfering RNA to NR4A2 decreases neutrophil production in this model. Antisense knockdown of NR4A2 and NR4A3 homologs in zebrafish larvae significantly reduces the absolute neutrophil number without affecting cellular migration. In summary, we show that NR4A2 and NR4A3 are components of a downstream transcriptional response to PKA activation in the neutrophil, and that they positively regulate neutrophil survival and homeostasis.

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Extracellular NAD+ inhibits human neutrophil apoptosis

Cited by 18 publications

References 51 publications

β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells

β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells

A critical look at the function of the P2Y11 receptor

NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival

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