TY - JOUR T1 - NAMPT-derived NAD<sup>+</sup> fuels PARP1 to promote skin inflammation through parthanatos JF - bioRxiv DO - 10.1101/2021.02.19.431942 SP - 2021.02.19.431942 AU - Francisco J. Martínez-Morcillo AU - Joaquín Cantón-Sandoval AU - Francisco J. Martínez-Navarro AU - Isabel Cabas AU - Idoya Martínez-Vicente AU - Joy Armistead AU - Julia Hatzold AU - Azucena López-Muñoz AU - Teresa Martínez-Menchón AU - Raúl Corbalán-Vélez AU - Jesús Lacal AU - Matthias Hammerschmidt AU - José C. García-Borrón AU - Alfonsa García-Ayala AU - María L. Cayuela AU - Ana B. Pérez-Oliva AU - Diana García-Moreno AU - Victoriano Mulero Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/02/22/2021.02.19.431942.abstract N2 - Several studies have revealed a correlation between chronic inflammation and 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 expression of pathology-associated genes in human organotypic 3D skin models of psoriasis. Consistently, an aberrant induction of both NAMPT amounts and PARP activity 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.HighlightsNAMPT inhibition alleviates inflammation in zebrafish and human epidermis organoid models of psoriasis.NADPH oxidase-derived ROS mediates keratinocyte DNA damage and Parp1 overactivation.Inhibition of parthanatos cell death phenocopies the effects of NAMPT inhibition in zebrafish and human psoriasis models.NAMPT and PAR metabolism is altered in psoriasis patients. ER -