Martinez-Morcillo, Francisco J., Canton-Sandoval, Joaquin, Martinez-Navarro, Francisco J., Cabas, Isabel, Martinez-Vicente, Idoya ORCID: 0000-0002-6949-6839, Armistead, Joy, Hatzold, Julia, Lopez-Munoz, Azucena, Martinez-Menchon, Teresa, Corbalan-Velez, Raul, Lacal, Jesus ORCID: 0000-0002-2751-7291, Hammerschmidt, Matthias, Garcia-Borron, Jose C., Garcia-Ayala, Alfonsa, Cayuela, Maria L., Perez-Oliva, Ana B., Garcia-Moreno, Diana and Mulero, Victoriano (2021). NAMPT-derived NAD(+) fuels PARP1 to promote skin inflammation through parthanatos cell death. PLoS. Biol., 19 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1545-7885

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Martinez-Morcillo, Francisco J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Canton-Sandoval, JoaquinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martinez-Navarro, Francisco J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cabas, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martinez-Vicente, IdoyaUNSPECIFIEDorcid.org/0000-0002-6949-6839UNSPECIFIED
Armistead, JoyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hatzold, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Munoz, AzucenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martinez-Menchon, TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Corbalan-Velez, RaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lacal, JesusUNSPECIFIEDorcid.org/0000-0002-2751-7291UNSPECIFIED
Hammerschmidt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Borron, Jose C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Ayala, AlfonsaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cayuela, Maria L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez-Oliva, Ana B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Moreno, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mulero, VictorianoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-587564
DOI: 10.1371/journal.pbio.3001455
Journal or Publication Title: PLoS. Biol.
Volume: 19
Number: 11
Date: 2021
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1545-7885
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ATOPIC-DERMATITIS; N-ACETYLCYSTEINE; METABOLISM; PSORIASIS; INHIBITION; ACTIVATION; MECHANISMS; APOPTOSISMultiple languages
Biochemistry & Molecular Biology; BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/58756

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