Enhanced NAMPT-Mediated NAD Salvage Pathway Contributes to Psoriasis Pathogenesis by Amplifying Epithelial Auto-Inflammatory Circuits
| Autor: | Claudia Scarponi, Cristina Albanesi, Sabatino Pallotta, Stefania Madonna, Martina Morelli, Laura Mercurio, Daniele Avitabile, Giovanni Luca Scaglione |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Chemokine NAMPT Biology (General) Nicotinamide Phosphoribosyltransferase Spectroscopy biology General Medicine Middle Aged Immunohistochemistry Computer Science Applications Chemistry Cytokines Female Disease Susceptibility Inflammation Mediators medicine.symptom Signal Transduction Adult keratinocytes QH301-705.5 NAD salvage pathway Inflammation Article Catalysis Inorganic Chemistry Paracrine signalling Immune system Downregulation and upregulation visfatin Psoriasis medicine Humans Physical and Theoretical Chemistry QD1-999 Molecular Biology Aged business.industry Organic Chemistry Endothelial Cells Fibroblasts NAD medicine.disease resident skin cells psoriasis inflammation biology.protein Cancer research Secukinumab NAD+ kinase business Biomarkers |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences; Volume 22; Issue 13; Pages: 6860 International Journal of Molecular Sciences, Vol 22, Iss 6860, p 6860 (2021) |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |