PUBLICATION
NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death
- Authors
- Martínez-Morcillo, F.J., Cantón-Sandoval, J., Martínez-Navarro, F.J., Cabas, I., Martínez-Vicente, I., Armistead, J., Hatzold, J., López-Muñoz, A., Martínez-Menchón, T., Corbalán-Vélez, R., Lacal, J., Hammerschmidt, M., García-Borrón, J.C., García-Ayala, A., Cayuela, M.L., Pérez-Oliva, A.B., García-Moreno, D., Mulero, V.
- ID
- ZDB-PUB-211109-21
- Date
- 2021
- Source
- PLoS Biology 19: e3001455 (Journal)
- Registered Authors
- Hammerschmidt, Matthias, Hatzold, Julia, Mulero, Victor
- Keywords
- none
- MeSH Terms
-
- Animals
- NADPH Oxidases/antagonists & inhibitors
- NADPH Oxidases/metabolism
- Apoptosis Inducing Factor/metabolism
- Inflammation/genetics
- Inflammation/pathology*
- Poly Adenosine Diphosphate Ribose/metabolism
- Gene Expression Regulation/drug effects
- Keratinocytes/drug effects
- Keratinocytes/metabolism
- Keratinocytes/pathology
- DNA Damage
- Poly(ADP-ribose) Polymerases/metabolism*
- Zebrafish
- Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
- Cell Nucleus/drug effects
- Cell Nucleus/metabolism
- Oxidative Stress/drug effects
- Oxidative Stress/genetics
- Larva/metabolism
- NAD/metabolism*
- Reactive Oxygen Species/metabolism
- Disease Models, Animal
- Proteinase Inhibitory Proteins, Secretory/deficiency
- Proteinase Inhibitory Proteins, Secretory/metabolism
- Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors
- Nicotinamide Phosphoribosyltransferase/metabolism*
- Parthanatos*/drug effects
- Parthanatos*/genetics
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/metabolism
- Psoriasis/genetics
- Psoriasis/pathology
- Skin/pathology*
- Cell Proliferation/drug effects
- PubMed
- 34748530 Full text @ PLoS Biol.
Citation
Martínez-Morcillo, F.J., Cantón-Sandoval, J., Martínez-Navarro, F.J., Cabas, I., Martínez-Vicente, I., Armistead, J., Hatzold, J., López-Muñoz, A., Martínez-Menchón, T., Corbalán-Vélez, R., Lacal, J., Hammerschmidt, M., García-Borrón, J.C., García-Ayala, A., Cayuela, M.L., Pérez-Oliva, A.B., García-Moreno, D., Mulero, V. (2021) NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death. PLoS Biology. 19:e3001455.
Abstract
Several studies have revealed a correlation between chronic inflammation and nicotinamide adenine dinucleotide (NAD+) metabolism, but the precise mechanism involved is unknown. Here, we report that the genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, reduced oxidative stress, inflammation, and keratinocyte DNA damage, hyperproliferation, and cell death in zebrafish models of chronic skin inflammation, while all these effects were reversed by NAD+ supplementation. Similarly, genetic and pharmacological inhibition of poly(ADP-ribose) (PAR) polymerase 1 (Parp1), overexpression of PAR glycohydrolase, inhibition of apoptosis-inducing factor 1, inhibition of NADPH oxidases, and reactive oxygen species (ROS) scavenging all phenocopied the effects of Nampt inhibition. Pharmacological inhibition of NADPH oxidases/NAMPT/PARP/AIFM1 axis decreased the expression of pathology-associated genes in human organotypic 3D skin models of psoriasis. Consistently, an aberrant induction of NAMPT and PARP activity, together with AIFM1 nuclear translocation, was observed in lesional skin from psoriasis patients. In conclusion, hyperactivation of PARP1 in response to ROS-induced DNA damage, fueled by NAMPT-derived NAD+, mediates skin inflammation through parthanatos cell death.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping