NAD<sup>+</sup>prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages

Iske, Jasper; Re, Fatimy; Nian, Yeqi; Sk, Eskandari; Hr, Cetina Biefer; Vasudevan, Anju; Elkhal, Abdallah

doi:10.1101/2020.03.29.013649

Cited by 3 publications

(2 citation statements)

References 54 publications

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“…Consistent with our results, previous works have shown that boosting NAD+ levels by administering NAD+ or other NAD+ biosynthetic precursors (i.e., Niacin, NAM, and NR) alleviates the polymicrobial sepsis in different animal models. Indeed, it has been shown that the treatment with a high dose of NAD+ prior to a lethal dose of E. coli or LPS resulted in a marked increase in survival in mice ( Iske et al, 2020 ). Furthermore, administration of high-dose of Niacin to rats subjected to LPS-induced endotoxemia attenuated lung inflammation, reduced histologic lung damages, and improved survival at 72 h post injection ( Kwon et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide Mononucleotide Administration Triggers Macrophages Reprogramming and Alleviates Inflammation During Sepsis Induced by Experimental Peritonitis

Cros¹,

Margier²,

Cannelle³

et al. 2022

Front. Mol. Biosci.

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Peritonitis and subsequent sepsis lead to high morbidity and mortality in response to uncontrolled systemic inflammation primarily mediated by macrophages. Nicotinamide adenine dinucleotide (NAD+) is an important regulator of oxidative stress and immunoinflammatory responses. However, the effects of NAD+ replenishment during inflammatory activation are still poorly defined. Hence, we investigated whether the administration of β-nicotinamide mononucleotide (β-NMN), a natural biosynthetic precursor of NAD+, could modulate the macrophage phenotype and thereby ameliorate the dysregulated inflammatory response during sepsis. For this purpose, C57BL6 mice were subjected to the cecal ligation and puncture (CLP) model to provoke sepsis or were injected with thioglycolate to induce sterile peritonitis with recruitment and differentiation of macrophages into the inflamed peritoneal cavity. β-NMN was administered for 4 days after CLP and for 3 days post thioglycolate treatment where peritoneal macrophages were subsequently analyzed. In the CLP model, administration of β-NMN decreased bacterial load in blood and reduced clinical signs of distress and mortality during sepsis. These results were supported by transcriptomic analysis of hearts and lungs 24 h post CLP-induction, which revealed that β-NMN downregulated genes controlling the immuno-inflammatory response and upregulated genes involved in bioenergetic metabolism, mitochondria, and autophagy. In the thioglycolate model, a significant increase in the proportion of CD206 macrophages, marker of anti-inflammatory M2 phenotype, was detected on peritoneal exudate macrophages from β-NMN-administered mice. Transcriptomic signature of these macrophages after bacterial stimulation confirmed that β-NMN administration limited the pro-inflammatory M1 phenotype and induced the expression of specific markers of M2 type macrophages. Furthermore, our data show that β-NMN treatment significantly impacts NAD + metabolism. This shift in the macrophage phenotype and metabolism was accompanied by a reduction in phagolysosome acidification and secretion of inflammatory mediators in macrophages from β-NMN-treated mice suggesting a reduced pro-inflammatory activation. In conclusion, administration of β-NMN prevented clinical deterioration and improved survival during sepsis. These effects relied on shifts in the metabolism of organs that face up an increased energy requirement caused by bacterial infection and in innate immunity response, including reprogramming of macrophages from a highly inflammatory phenotype to an anti-inflammatory/pro-resolving profile.

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Section: Discussionmentioning

confidence: 99%

Nicotinamide Mononucleotide Administration Triggers Macrophages Reprogramming and Alleviates Inflammation During Sepsis Induced by Experimental Peritonitis

Cros¹,

Margier²,

Cannelle³

et al. 2022

Front. Mol. Biosci.

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“…Intracellular NAMPT converts nicotinamide to nicotinamide mononucleotide and is responsible for most of the NAD+ formation in mammals. Administration of NAD + prevents murine septic shock [34]. Extracellular NAMPT activates TLR4, promotes B cell maturation, and inhibits neutrophil apoptosis [35].…”

Section: Discussionmentioning

confidence: 99%

Genetic variants associated with sepsis

et al. 2022

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Background The variable presentations and different phenotypes of sepsis suggest that risk of sepsis comes from many genes each having a small effect. The cumulative effect can be used to create individual risk profile. The purpose of this study was to create a polygenic risk score and determine the genetic variants associated with sepsis. Methods We sequenced ~14 million single nucleotide polymorphisms with a minimac imputation quality R2>0.3 and minor allele frequency >10−6 in patients with Sepsis-2 or Sepsis-3. Genome-wide association was performed using Firth bias-corrected logistic regression. Semi-parsimonious logistic regression was used to create polygenic risk scores and reduced regression to determine the genetic variants independently associated with sepsis. Findings 2261 patients had sepsis and 13,068 control patients did not. The polygenic risk scores had good discrimination: c-statistic = 0.752 ± 0.005 for Sepsis-2 and 0.752 ± 0.007 for Sepsis-3. We found 772 genetic variants associated with Sepsis-2 and 442 with Sepsis-3, p<0.01. After multivariate adjustment, 100 variants on 85 genes were associated with Sepsis-2 and 69 variants in 54 genes with Sepsis-3. Twenty-five variants were present in both the Sepsis-2 and Sepsis-3 groups out of 32 genes that were present in both groups. The other 7 genes had different variants present. Most variants had small effect sizes. Conclusions Sepsis-2 and Sepsis-3 have both separate and shared genetic variants. Most genetic variants have small effects sizes, but cumulatively, the polygenic risk scores have good discrimination.

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NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis

Zhao

Wang

et al. 2022

Nat. Nanotechnol.

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NAD⁺prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages

Cited by 3 publications

References 54 publications

Nicotinamide Mononucleotide Administration Triggers Macrophages Reprogramming and Alleviates Inflammation During Sepsis Induced by Experimental Peritonitis

Nicotinamide Mononucleotide Administration Triggers Macrophages Reprogramming and Alleviates Inflammation During Sepsis Induced by Experimental Peritonitis

Genetic variants associated with sepsis

NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis

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NAD+prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages

Cited by 3 publications

References 54 publications

Nicotinamide Mononucleotide Administration Triggers Macrophages Reprogramming and Alleviates Inflammation During Sepsis Induced by Experimental Peritonitis

Nicotinamide Mononucleotide Administration Triggers Macrophages Reprogramming and Alleviates Inflammation During Sepsis Induced by Experimental Peritonitis

Genetic variants associated with sepsis

NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis

Contact Info

Product

Resources

About

NAD⁺prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages