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

ABSTRACT: 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.

SUBMITTER: Mercurio L

PROVIDER: S-EPMC8267663 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND Current treatment of glioblastoma (GBM) with surgery and chemoRT yields an average survival of ~1.5 years, highlighting the need for more effective therapies. We have previously reported that PAK4 is a key modulator of radioresistance in GBM. Additionally, pathways that regulate differential energy metabolism in gliomas and circumvent tumor heterogeneity have recently emerged as promising therapeutic targets. We hypothesized that inhibition of NAMPT, the rate-limiting enzyme of the NAD+ salvage pathway, a key pathway preferentially used in glioma energy metabolism, would be effective against GBM. METHODS We tested the efficacy of KPT9274, a potent first-in-class dual inhibitor of PAK4 and NAMPT, currently in human trials against solid tumors and lymphomas (NCT02702492), on NAD levels and cell viability in glioma cell lines and patient-derived glioma stem-like cells (GSC). We also examined enzyme-kinetics of various components of the NAD salvage pathway and effects of NADH rescue by nicotinamide, NMN and NAD. Lastly, we examined the biological relevance of NAMPT inhibition in glioma cells and GSC using a combination of cell adhesion, wound-healing, transwell-migration and microtubule formation assays. RESULTS Treatment with KPT9274 resulted in potent depletion of NAD in glioma cells which was rescued by nicotinamide, NMN and NAD demonstrating its specificity against NAMPT. KPT-9274 treatment resulted in potent inhibition of cell adhesion, migration, cell invasion, endothelial tube formation and proliferation in glioma cells and GSC. In vivo studies in mouse bioluminescent intracranial glioma PDX model as well as PK studies are ongoing to confirm the pre-clinical significance of targeting NAMPT in gliomas and will be presented. CONCLUSIONS Our study demonstrates a key role for NAMPT in NAD generation in gliomas as seen by the potent biological effects of KPT-9274 against these tumors and supports the potential for targeting the NAD salvage pathway as a novel therapeutic strategy for treatment of GBM.

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

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