Low Cellular NAD+ Compromises Lipopolysaccharide-Induced Inflammatory Responses via Inhibiting TLR4 Signal Transduction in Human Monocytes

Yang, Kuan; Lauritzen, Knut H.; Olsen, Maria Belland; Dahl, Tuva B.; Ranheim, Trine; Ahmed, Mohammed S.; Attramadal, Håvard; Aukrust, Pål; Halvorsen, Bente; Nyman, Tuula A.; Sandanger, Øystein; Yndestad, Arne

doi:10.4049/jimmunol.1801382

Cited by 33 publications

(29 citation statements)

References 44 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, adding NAD + to cultured macrophages increased M2 polarization and the expression levels of IL‐1ra and IL‐10, which are anti‐inflammatory (with no effect on M1). Somewhat consistent with these findings are the recent observations that intracellular NAMPT and NAD + appear to be necessary for activation of the major protein component of the inflammasome (NLRP3) of human primary monocytes, which are precursors of macrophages 163 . Their contribution was attributed to the maintenance of TLR4 signal transduction, which is critical as a priming signal for the NLRP3 inflammasome, specifically their importance for TLR4‐induced phosphorylation of several downstream proteins in the MyD88‐dependent signal pathway.…”

Section: The Relationship Between Nad Levels Enzymes Synthesizing Orsupporting

confidence: 65%

Nicotinamide adenine dinucleotide: Biosynthesis, consumption and therapeutic role in cardiac diseases

et al. 2020

View full text Add to dashboard Cite

Nicotinamide adenine dinucleotide (NAD) is an abundant cofactor that plays crucial roles in several cellular processes. NAD can be synthesized de novo starting with tryptophan, or from salvage pathways starting with NAD precursors like nicotinic acid (NA), nicotinamide (NAM) or nicotinamide riboside (NR), referred to as niacin/B3 vitamins, arising from dietary supply or from cellular NAD catabolism. Given the interconversion between its oxidized (NAD+) and reduced form (NADH), NAD participates in a wide range of reactions: regulation of cellular redox status, energy metabolism and mitochondrial biogenesis. Plus, NAD acts as a signalling molecule, being a cosubstrate for several enzymes such as sirtuins, poly‐ADP‐ribose‐polymerases (PARPs) and some ectoenzymes like CD38, regulating critical biological processes like gene expression, DNA repair, calcium signalling and circadian rhythms. Given the large number of mitochondria present in cardiac tissue, the heart has the highest NAD levels and is one of the most metabolically demanding organs. In several models of heart failure, myocardial NAD levels are depressed and this depression is caused by mitochondrial dysfunction, metabolic remodelling and inflammation. Emerging evidence suggests that regulating NAD homeostasis by NAD precursor supplementation has therapeutic efficiency in improving myocardial bioenergetics and function. This review provides an overview of the latest understanding of the different NAD biosynthesis pathways, as well as its role as a signalling molecule particularly in cardiac tissue. We highlight the significance of preserving NAD equilibrium in various models of heart diseases and shed light on the potential pharmacological interventions aiming to use NAD boosters as therapeutic agents.

show abstract

Section: The Relationship Between Nad Levels Enzymes Synthesizing Orsupporting

confidence: 65%

Nicotinamide adenine dinucleotide: Biosynthesis, consumption and therapeutic role in cardiac diseases

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Evidence shows that elevated levels of intracellular NAD + enhance IL-1β secretion. Additionally, this study found that sirtuin inhibition did not suppress NLRP3 inflammasome activity, and low levels of NAD + were found to inhibit IL-1β secretion [130]. Further investigation into this discrepancy is needed.…”

Section: Acetylation and Nad Cyclingmentioning

confidence: 78%

The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging

Meyers

Zhu

2020

Cells

123

100

View full text Add to dashboard Cite

In response to inflammatory stimuli, immune cells reconfigure their metabolism and bioenergetics to generate energy and substrates for cell survival and to launch immune effector functions. As a critical component of the innate immune system, the nucleotide-binding and oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome can be activated by various endogenous and exogenous danger signals. Activation of this cytosolic multiprotein complex triggers the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and initiates pyroptosis, an inflammatory form of programmed cell death. The NLRP3 inflammasome fuels both chronic and acute inflammatory conditions and is critical in the emergence of inflammaging. Recent advances have highlighted that various metabolic pathways converge as potent regulators of the NLRP3 inflammasome. This review focuses on our current understanding of the metabolic regulation of the NLRP3 inflammasome activation, and the contribution of the NLRP3 inflammasome to inflammaging.

show abstract

“…More recently, the same group that firstly identified TLR4 as NAMPT receptor published new details about this interaction (155). At the same time, a direct role of NAD in activating the inflammasome was recently reported by Yang et al The authors demonstrated that NAD manipulation, using NAMPT inhibitors or the treatment with NAD precursors, affects TLR4-mediated NF-κB activation and PYD-domain 3 (NLRP3) inflammasome activity connecting intracellular NAD levels and inflammation (156).…”

Section: Enampt/enaprt In Myeloid Cells Function: the Role Of Tlr4mentioning

confidence: 95%

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

2020

View full text Add to dashboard Cite

Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT) are two intracellular enzymes that catalyze the first step in the biosynthesis of NAD from nicotinamide and nicotinic acid, respectively. By fine tuning intracellular NAD levels, they are involved in the regulation/reprogramming of cellular metabolism and in the control of the activity of NAD-dependent enzymes, including sirtuins, PARPs, and NADases. However, during evolution they both acquired novel functions as extracellular endogenous mediators of inflammation. It is well-known that cellular stress and/or damage induce release in the extracellular milieu of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs), which modulate immune functions through binding pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), and activate inflammatory responses. Increasing evidence suggests that extracellular (e)NAMPT and eNAPRT are novel soluble factors with cytokine/adipokine/DAMP-like actions. Elevated eNAMPT were reported in several metabolic and inflammatory disorders, including obesity, diabetes, and cancer, while eNAPRT is emerging as a biomarker of sepsis and septic shock. This review will discuss available data concerning the dual role of this unique family of enzymes.

show abstract

Low Cellular NAD+ Compromises Lipopolysaccharide-Induced Inflammatory Responses via Inhibiting TLR4 Signal Transduction in Human Monocytes

Abstract: This information is current as Transduction in Human Monocytes Responses via Inhibiting TLR4 Signal Lipopolysaccharide-Induced Inflammatory Compromises + Low Cellular NAD

Cited by 33 publications

References 44 publications

Nicotinamide adenine dinucleotide: Biosynthesis, consumption and therapeutic role in cardiac diseases

Nicotinamide adenine dinucleotide: Biosynthesis, consumption and therapeutic role in cardiac diseases

The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

Contact Info

Product

Resources

About