NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death

Francisco J Martínez-Morcillo, Joaquín Cantón-Sandoval, Francisco J Martínez-Navarro, Isabel Cabas, Idoya Martínez-Vicente, Joy Armistead, Julia Hatzold, Azucena López-Muñoz, Teresa Martínez-Menchón, Raúl Corbalán-Vélez, Jesús Lacal, Matthias Hammerschmidt, José C García-Borrón, Alfonsa García-Ayala, María L Cayuela, Ana B Pérez-Oliva, Diana García-Moreno and Victoriano Mulero

PLOS Biology, 2021, vol. 19, issue 11, 1-27

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.A study of chronic skin inflammation reveals that hyperactivation of PARP1 in response to ROS-induced DNA damage, fueled by NAMPT-derived NAD+, mediates skin inflammation via parthanatos cell death, identifying NAMPT, PARP1 and AIFM1 as novel therapeutic targets for psoriasis.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pbio00:3001455

DOI: 10.1371/journal.pbio.3001455

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