Neutralization of extracellular NAMPT (nicotinamide phosphoribosyltransferase) ameliorates experimental murine colitis

Colombo, Giorgia; Clemente, Nausicaa; Zito, Andrea; Bracci, Cristiano; Colombo, Federico; Sangaletti, Sabina; Jachetti, Elena; Ribaldone, Davide Giuseppe; Caviglia, Gian Paolo; Pastorelli, Luca; Andrea, Marco De; Naviglio, Samuele; Lucafò, Marianna; Stocco, Gabriele; Grolla, Ambra A.; Campolo, Michela; Casili, Giovanna; Cuzzocrea, Salvatore; Esposito, Emanuela; Malavasi, Fabio; Genazzani, Armando A.; Porta, Chiara; Travelli, Cristina

doi:10.1007/s00109-020-01892-0

Cited by 38 publications

(58 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These differences were more evident with medium conditioned by fibroblasts, in line with the higher release of eNAMPT observed in untreated and IFN-γ/TNF-α-treated sups of fibroblasts (untreated 23.3 ± 4.5 ng/10 6 cells vs. treated 48 ± 2.5 ng/10 6 cells) compared to those observed in sups of keratinocytes (untreated 4.6 ± 0.5 ng/10 6 cells vs. treated 10.1 ± 1.5 ng/10 6 cells). Similar results were obtained by neutralizing the extracellular NAMPT released by fibroblasts and keratinocytes with a newly generated monoclonal antibody (C269) able to neutralize the cytokine-like action of eNAMPT in vitro and in vivo [54]. These results confirm the pro-proliferative activity of the extracellular NAMPT released by skin resident cells on dermal endothelial cells.…”

Section: Nampt Is Strongly Released By Activated Keratinocytes and Fibroblasts And Induces Proliferation And Inflammation In Dermal Endotsupporting

confidence: 81%

“…Other than in epithelial compartment, NAMPT expression is also enhanced in peripheral blood mononuclear cells of patients with severe psoriasis [66], indicating its involvement in systemic inflammation mediated by circulating immune cells. Moreover, NAMPT is systemically elevated in patients with rheumatoid arthritis [67,68] or inflammatory bowel diseases [54]. Specific inhibitors or antibodies blocking NAMPT ameliorate the immune-mediated inflammation of experimental models of acute and chronic colitis and collagen-induced arthritis, by reducing intracellular NAD + levels in inflammatory cells and circulating inflammatory cytokines [54,69,70].…”

Section: Figurementioning

confidence: 99%

“…Moreover, NAMPT is systemically elevated in patients with rheumatoid arthritis [67,68] or inflammatory bowel diseases [54]. Specific inhibitors or antibodies blocking NAMPT ameliorate the immune-mediated inflammation of experimental models of acute and chronic colitis and collagen-induced arthritis, by reducing intracellular NAD + levels in inflammatory cells and circulating inflammatory cytokines [54,69,70]. The potential anti-inflammatory effects of intracellular NAMPT inhibitors and/or neutralizing NAMPT antibodies will be further investigated in experimental murine models of psoriasis.…”

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Enhanced NAMPT-Mediated NAD Salvage Pathway Contributes to Psoriasis Pathogenesis by Amplifying Epithelial Auto-Inflammatory Circuits

Mercurio

Morelli

Scarponi

et al. 2021

IJMS

View full text Add to dashboard Cite

Dysregulated cross-talk between immune cells and epithelial compartments is responsible for the onset and amplification of pathogenic auto-inflammatory circuits occurring in psoriasis. NAMPT-mediated NAD salvage pathway has been recently described as an immunometabolic route having inflammatory function in several disorders, including arthritis and inflammatory bowel diseases. To date, the role of NAD salvage pathway has not been explored in the skin of patients affected by psoriasis. Here, we show that NAD content is enhanced in lesional skin of psoriatic patients and is associated to high NAMPT transcriptional levels. The latter are drastically reduced in psoriatic skin following treatment with the anti-IL-17A biologics secukinumab. We provide evidence that NAMPT-mediated NAD+ metabolism fuels the immune responses executed by resident skin cells in psoriatic skin. In particular, intracellular NAMPT, strongly induced by Th1/Th17-cytokines, acts on keratinocytes by inducing hyper-proliferation and impairing their terminal differentiation. Furthermore, NAMPT-mediated NAD+ boosting synergizes with psoriasis-related cytokines in the upregulation of inflammatory chemokines important for neutrophil and Th1/Th17 cell recruitment. In addition, extracellular NAMPT, abundantly released by keratinocytes and dermal fibroblasts, acts in a paracrine manner on endothelial cells by inducing their proliferation and migration, as well as the expression of ICAM-1 membrane molecule and chemokines important for leukocyte recruitment into inflamed skin. In conclusion, our results showed that NAMPT-mediated NAD salvage pathway contributes to psoriasis pathogenic processes by amplifying epithelial auto-inflammatory responses in psoriasis.

show abstract

Section: Nampt Is Strongly Released By Activated Keratinocytes and Fibroblasts And Induces Proliferation And Inflammation In Dermal Endotsupporting

confidence: 81%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Enhanced NAMPT-Mediated NAD Salvage Pathway Contributes to Psoriasis Pathogenesis by Amplifying Epithelial Auto-Inflammatory Circuits

Mercurio

Morelli

Scarponi

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…action of eNAMPT and that reduces its serum levels in rodents. Of note, this newly generated antibody is able to significantly reduce acute and chronic colitis in both DNBS-and dextran sodium sulphate-(DSS) induced colitis (Colombo et al, 2020), demonstrating the eNAMPT participation in inflammatory bowel disease (IBD) and the therapeutic potential of its neutralization in this pathology. While no data are at present available in cancer, there are ample evidences that the extracellular form is involved (as described above and in (Grolla et al, 2015;Dalamaga et al, 2018;Travelli et al, 2018;Audrito et al, 2019;Ji et al, 2019); and it would be a worthwhile effort to verify its neutralization in this field.…”

Section: Strategies To Target the Extracellular Form Of Namptmentioning

confidence: 99%

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

et al. 2020

Self Cite

View full text Add to dashboard Cite

Nicotinamide adenine dinucleotide (NAD) is a cofactor of many enzymatic reactions as well as being a substrate for a number of NAD-consuming enzymes (e.g., PARPS, sirtuins, etc). NAD can be synthesized de novo starting from tryptophan, nicotinamide, nicotinic acid, or nicotinamide riboside from the diet. On the other hand, the nicotinamide that is liberated by NAD-consuming enzymes can be salvaged to reform NAD. In this former instance, nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme. In the many cells in which the salvage pathway is predominant, NAMPT, therefore, represents an important controller of intracellular NAD concentrations, and as a consequence of energy metabolism. It is, therefore, not surprising that NAMPT is over expressed by tumoral cells, which take advantage from this to sustain growth rate and tumor progression. This has led to the initiation of numerous medicinal chemistry programs to develop NAMPT inhibitors in the context of oncology. More recently, however, it has been shown that NAMPT inhibitors do not solely target the tumor but also have an effect on the immune system. To add complexity, this enzyme can also be secreted by cells, and in the extracellular space it acts as a cytokine mainly through the activation of Toll like Receptor 4 (TLR4), although it has not been clarified yet if this is the only receptor responsible for its actions. While specific small molecules have been developed only against the intracellular form of NAMPT, growing evidences sustain the possibility to target the extracellular form. In this contribution, the most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NAMPT targeting and the drawbacks so far encountered.

show abstract

“…Moreover, a proinflammatory function of eNAMPT has already been established [ 92 ]. Consistently, serum levels of eNAMPT were found to be elevated in inflammatory bowel disease (IBD) patients who showed resistance to anti-TNFα therapy, and eNAMPT neutralization, with an anti-eNAMPT monoclonal antibody, ameliorated acute and chronic colitis in experimental mice models [ 93 ]. Notably, NAPRT was also found to exist as an extracellular protein (eNAPRT), which mediates inflammation by binding to toll-like receptor 4 (TLR4) and by activating the NF-κB pathway [ 94 ].…”

Section: Chemical Inhibitors Of Nad Biosynthesismentioning

confidence: 99%

Advances in NAD-Lowering Agents for Cancer Treatment

2021

View full text Add to dashboard Cite

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor, but it also acts as a substrate for NAD-consuming enzymes, regulating cellular events such as DNA repair and gene expression. Since such processes are fundamental to support cancer cell survival and proliferation, sustained NAD production is a hallmark of many types of neoplasms. Depleting intratumor NAD levels, mainly through interference with the NAD-biosynthetic machinery, has emerged as a promising anti-cancer strategy. NAD can be generated from tryptophan or nicotinic acid. In addition, the “salvage pathway” of NAD production, which uses nicotinamide, a byproduct of NAD degradation, as a substrate, is also widely active in mammalian cells and appears to be highly exploited by a subset of human cancers. In fact, research has mainly focused on inhibiting the key enzyme of the latter NAD production route, nicotinamide phosphoribosyltransferase (NAMPT), leading to the identification of numerous inhibitors, including FK866 and CHS-828. Unfortunately, the clinical activity of these agents proved limited, suggesting that the approaches for targeting NAD production in tumors need to be refined. In this contribution, we highlight the recent advancements in this field, including an overview of the NAD-lowering compounds that have been reported so far and the related in vitro and in vivo studies. We also describe the key NAD-producing pathways and their regulation in cancer cells. Finally, we summarize the approaches that have been explored to optimize the therapeutic response to NAMPT inhibitors in cancer.

show abstract

Neutralization of extracellular NAMPT (nicotinamide phosphoribosyltransferase) ameliorates experimental murine colitis

Cited by 38 publications

References 47 publications

Enhanced NAMPT-Mediated NAD Salvage Pathway Contributes to Psoriasis Pathogenesis by Amplifying Epithelial Auto-Inflammatory Circuits

Enhanced NAMPT-Mediated NAD Salvage Pathway Contributes to Psoriasis Pathogenesis by Amplifying Epithelial Auto-Inflammatory Circuits

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

Advances in NAD-Lowering Agents for Cancer Treatment

Contact Info

Product

Resources

About