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.

Determining the link between psoriasis and Crohn's disease using bioinformatics and systems biology approaches

“…In this capacity NAMPT triggers the activation of cells by binding to receptors 49 leading to the release of in ammatory factors and contributing to in ammation processes. Studies indicate that the modulation of NAD + metabolism by NAMPT enhances skin immunity responses 50,51 in conditions, like psoriasis. Another study suggest NAMPT's role in Crohn's disease 52 .…”

Predictive value of adipokines for the severity of acute pancreatitis: a meta-analysis

“…Visfatin has nicotinamide phosphoribose transferase (Nampt) activity, the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) remedial synthesis pathway, and macrophages rely on the NAD remedial pathway to meet their energy requirements and maintain their proinflammatory phenotype, and visfatin promotes the release of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α from peripheral monocytes [17][18][19]. Interestingly, visfatin appears to have antiinflammatory [42][43][44] as well as pro-inflammatory effects [17][18][19][45][46][47][48]. In response to this seemingly contradictory result, the study by Sayers et al may give us some insight.…”

PARPs and ADP-Ribosylation in Chronic Inflammation: A Focus on Macrophages

“…They found that depletion of NAD+ reduced PARP1/ARTD1 catalytic activity, suppressed the expression of IL-6, IL-1β, and TNF-α, and skewed monocytes/macrophages from pro-inflammatory towards anti-inflammatory phenotypes [ 56 ]. In the same line, reduction of NAMPT-derived NAD+ via pharmacological inhibition of NAMPT reduced the pathological changes in psoriasis [ 57 ] and atopic dermatitis [ 58 ] and diminished the expression of pro-inflammatory biomarkers.…”

“…Activity Disease/Biological Process(s) PARP1/ARTD1 PARylation, MARylation, or non-catalytic activity Emphysema/Chronic lung inflammation [49,50] H. pylori infection [51] Colitis/Inflammatory bowel diseases [53,54,56] Psoriasis [57,66] Atopic dermatitis [58] Alcoholic liver injury [63] Chagas heart disease [69][70][71][72] PARP7/ARTD14 MARylation SARS-CoV-2 infection [23] Colitis/Inflammatory bowel diseases [53,54,56] PARP9/ARTD9 MARylation Pulmonary tuberculosis [83,84] RNA-viruses infections [85,86] Atherosclerosis/arterial inflammation [79,80] SARS-CoV-2 infection [117] PARP10/ARTD10 MARylation SARS-CoV-2 infection [23] Arboviruses infections [88] PARP12/ARTD12 MARylation Assembly and maintenance of stress granules [15] SARS-CoV-2 infection [23] PARP13/ARTD13 Non-catalytic activity Assembly and maintenance of stress granules [15] Atherosclerosis/arterial inflammation [79,80,90,91] Arboviruses infections [88,89] PARP15/ARTD7 MARylation Assembly and maintenance of stress granules [15] Arboviruses infections [88] PARG Hydrolysis (PAR) Assembly and maintenance of stress granules [15,98] Macrodomain 1 (nsp3) Hydrolysis (MAR) SARS-CoV-2 infection …”