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

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...

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Autores principales:	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, Victoriano Mulero
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7eee5ee7fb2a4382a2dfaadd0d7636f1
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spelling	oai:doaj.org-article:7eee5ee7fb2a4382a2dfaadd0d7636f12021-11-25T05:33:35ZNAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death1544-91731545-7885https://doaj.org/article/7eee5ee7fb2a4382a2dfaadd0d7636f12021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601609/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Several 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.Francisco J. Martínez-MorcilloJoaquín Cantón-SandovalFrancisco J. Martínez-NavarroIsabel CabasIdoya Martínez-VicenteJoy ArmisteadJulia HatzoldAzucena López-MuñozTeresa Martínez-MenchónRaúl Corbalán-VélezJesús LacalMatthias HammerschmidtJosé C. García-BorrónAlfonsa García-AyalaMaría L. CayuelaAna B. Pérez-OlivaDiana García-MorenoVictoriano MuleroPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 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 Victoriano Mulero NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death
description	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.
format	article
author	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 Victoriano Mulero
author_facet	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 Victoriano Mulero
author_sort	Francisco J. Martínez-Morcillo
title	NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death
title_short	NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death
title_full	NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death
title_fullStr	NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death
title_full_unstemmed	NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death
title_sort	nampt-derived nad+ fuels parp1 to promote skin inflammation through parthanatos cell death
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/7eee5ee7fb2a4382a2dfaadd0d7636f1
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NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death

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