NAMPT inhibition relieves intestinal inflammation by regulating macrophage activation in experimental necrotizing enterocolitis

Liu, Qianyang; Gao, Xinbo; Ding, Xionghui; Mo, Dandan; Guo, Hongjie; Chen, Bailin; Xia, Bingshan; Ye, Cuilian; Chen, Gongli; Guo, Chunbao

doi:10.1016/j.biopha.2023.115012

Cited by 4 publications

(3 citation statements)

References 48 publications

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“…Both NAMPT and PARP1 have been associated with chronic inflammation, including enterocolitis [31] and rheumatoid arthritis, [32] while their roles in inflammatory pain remain unclear. In the present study, injecting either NAMPT or PARP1 siRNA i.t.…”

Section: Discussionmentioning

confidence: 99%

NAMPT/NAD⁺/PARP1 Pathway Regulates CFA‐Induced Inflammatory Pain via NF‐κB Signaling in Rodents

Dai,

Lin,

Chen

et al. 2024

Advanced Biology

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Emerging evidence has implicated nicotinamide adenine dinucleotide (NAD+) metabolism in various inflammatory diseases. In the study, the role of NAD+ metabolism in Complete Freund's Adjuvant (CFA)‐evoked inflammatory pain and the underlying mechanisms are investigated. The study demonstrated that CFA induced upregulation of nicotinamide phosphoribosyltransferase (NAMPT) in dorsal root ganglia (DRG) without significant changes in the spinal cord. Inhibition of NAMPT expression by intrathecal injection of NAMPT siRNA alleviated CFA‐induced pain‐like behavior, decreased NAD+ contents in DRG, and lowered poly‐(ADP‐ribose) polymerase 1 (PARP1) activity levels. These effects are all reversed by the supplement of nicotinamide mononucleotide (NMN). Inhibition of PARP1 expression by intrathecal injection of PARP1 siRNA alleviated CFA‐induced pain‐like behavior, while elevated NAD+ levels of DRG. The analgesic effect of inhibiting NAMPT/NAD+/PARP1 axis can be attributed to the downregulation of the NF‐κB/IL‐1β inflammatory pathway. Double immunofluorescence staining showed that the expression of NAMPT/NAD+/PARP1 axis is restricted to DRG neurons. In conclusion, PARP1 activation in response to CFA stimulation, fueled by NAMPT‐derived NAD+, mediates CFA‐induced inflammatory pain through NF‐κB/IL‐1β inflammatory pathway.

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Section: Discussionmentioning

confidence: 99%

NAMPT/NAD⁺/PARP1 Pathway Regulates CFA‐Induced Inflammatory Pain via NF‐κB Signaling in Rodents

Dai,

Lin,

Chen

et al. 2024

Advanced Biology

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“…This study provides compelling support for eNAMPT involvement in NEC pathobiology and eNAMPT neutralization as a novel therapeutic strategy in NEC. While the inhibition of intracellular NAMPT with FK866 has been shown to reduce NEC [90], we are the first to target eNAMPT in NEC using the eNAMPT-neutralizing mAb ALT-100. The safety of ALT-100 was validated in a completed phase 1A safety trial, and pharmacokinetic studies of a single IV-delivered ALT-100 dose (0.1-4 mg/kg) in healthy human volunteers showed the complete absence of serious adverse events, with a therapeutic half-life of 21-30 days.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Nicotinamide Phosphoribosyltransferase Is a Therapeutic Target in Experimental Necrotizing Enterocolitis

Halpern,

Gupta,

Zaghloul

et al. 2024

Biomedicines

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Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of prematurity. Postulated mechanisms leading to inflammatory necrosis of the ileum and colon include activation of the pathogen recognition receptor Toll-like receptor 4 (TLR4) and decreased levels of transforming growth factor beta (TGFβ). Extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a novel damage-associated molecular pattern (DAMP), is a TLR4 ligand and plays a role in a number of inflammatory disease processes. To test the hypothesis that eNAMPT is involved in NEC, an eNAMPT-neutralizing monoclonal antibody, ALT-100, was used in a well-established animal model of NEC. Preterm Sprague–Dawley pups delivered prematurely from timed-pregnant dams were exposed to hypoxia/hypothermia and randomized to control—foster mother dam-fed rats, injected IP with saline (vehicle) 48 h after delivery; control + mAB—foster dam-fed rats, injected IP with 10 µg of ALT-100 at 48 h post-delivery; NEC—orally gavaged, formula-fed rats injected with saline; and NEC + mAb—formula-fed rats, injected IP with 10 µg of ALT-100 at 48 h. The distal ileum was processed 96 h after C-section delivery for histological, biochemical, molecular, and RNA sequencing studies. Saline-treated NEC pups exhibited markedly increased fecal blood and histologic ileal damage compared to controls (q < 0.0001), and findings significantly reduced in ALT-100 mAb-treated NEC pups (q < 0.01). Real-time PCR in ileal tissues revealed increased NAMPT in NEC pups compared to pups that received the ALT-100 mAb (p < 0.01). Elevated serum levels of tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), interleukin-8 (IL-8), and NAMPT were observed in NEC pups compared to NEC + mAb pups (p < 0.01). Finally, RNA-Seq confirmed dysregulated TGFβ and TLR4 signaling pathways in NEC pups that were attenuated by ALT-100 mAb treatment. These data strongly support the involvement of eNAMPT in NEC pathobiology and eNAMPT neutralization as a strategy to address the unmet need for NEC therapeutics.

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“…Macrophages play a key role in TLR4-mediated induction of intestinal inflammation upon challenge with pathogen-associated molecular patterns (PAMPs) such as LPS ( 37 ). In this regard, their polarization towards pro-inflammatory M1- and tissue-homeostatic M2-phenotypes has been shown to be associated with the development of NEC, and modulation proposed as a possible treatment strategy for excessive gut-inflammation ( 38 , 39 ). As blood monocytes that migrate into the developing gut ( 40 , 41 ) encounter abundant hLF from colostrum, we aimed to investigate whether hLF modulates the function of these newly differentiating macrophages to prevent excessive gut inflammation upon LPS challenge, the main PAMP associated with gram-negative bacteria.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis identifies lactoferrin-induced quiescent circuits in neonatal macrophages

Eigenschink,

Wessely,

Dijmarescu

et al. 2023

Front. Immunol.

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IntroductionUpon birth, a hitherto naïve immune system is confronted with a plethora of microbial antigens due to intestinal bacterial colonization. To prevent excessive inflammation and disruption of the epithelial barrier, physiological mechanisms must promote immune-anergy within the neonatal gut. As high concentrations of human lactoferrin (hLF), a transferrin glycoprotein shown to modulate macrophage function, are frequently encountered in colostrum, its direct interaction with intestinal macrophages may satisfy this physiological need. Thus, the primary objective of this study was to investigate transcriptional changes induced by human lactoferrin in neonatal monocyte-derived macrophages.MethodsCord blood-derived monocytes were differentiated with M-CSF in presence or absence of 500 µg/mL hLF for 7 days and afterwards stimulated with 1 ng/mL LPS or left untreated. RNA was then isolated and subjected to microarray analysis.ResultsDifferentiation of cord blood-derived monocytes in presence of hLF induced a distinct transcriptional program defined by cell cycle arrest in the G2/M phase, induction of IL-4/IL-13-like signaling, altered extracellular matrix interaction, and enhanced propensity for cell-cell interaction. Moreover, near-complete abrogation of transcriptional changes induced by TLR4 engagement with LPS was observed in hLF-treated samples.DiscussionThe global transition towards an M2-like homeostatic phenotype and the acquisition of quiescence elegantly demonstrate the ontogenetical relevance of hLF in attenuating pro-inflammatory signaling within the developing neonatal intestine. The marked anergy towards proinflammatory stimuli such as LPS further underlines the glycoprotein’s potential therapeutic relevance.

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NAMPT inhibition relieves intestinal inflammation by regulating macrophage activation in experimental necrotizing enterocolitis

Cited by 4 publications

References 48 publications

NAMPT/NAD⁺/PARP1 Pathway Regulates CFA‐Induced Inflammatory Pain via NF‐κB Signaling in Rodents

NAMPT/NAD⁺/PARP1 Pathway Regulates CFA‐Induced Inflammatory Pain via NF‐κB Signaling in Rodents

Extracellular Nicotinamide Phosphoribosyltransferase Is a Therapeutic Target in Experimental Necrotizing Enterocolitis

Transcriptomic analysis identifies lactoferrin-induced quiescent circuits in neonatal macrophages

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NAMPT inhibition relieves intestinal inflammation by regulating macrophage activation in experimental necrotizing enterocolitis

Cited by 4 publications

References 48 publications

NAMPT/NAD+/PARP1 Pathway Regulates CFA‐Induced Inflammatory Pain via NF‐κB Signaling in Rodents

NAMPT/NAD+/PARP1 Pathway Regulates CFA‐Induced Inflammatory Pain via NF‐κB Signaling in Rodents

Extracellular Nicotinamide Phosphoribosyltransferase Is a Therapeutic Target in Experimental Necrotizing Enterocolitis

Transcriptomic analysis identifies lactoferrin-induced quiescent circuits in neonatal macrophages

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NAMPT/NAD⁺/PARP1 Pathway Regulates CFA‐Induced Inflammatory Pain via NF‐κB Signaling in Rodents

NAMPT/NAD⁺/PARP1 Pathway Regulates CFA‐Induced Inflammatory Pain via NF‐κB Signaling in Rodents