In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 11 ( 2021-11-8), p. 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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001455
DOI:
10.1371/journal.pbio.3001455.g001
DOI:
10.1371/journal.pbio.3001455.g002
DOI:
10.1371/journal.pbio.3001455.g003
DOI:
10.1371/journal.pbio.3001455.g004
DOI:
10.1371/journal.pbio.3001455.g005
DOI:
10.1371/journal.pbio.3001455.g006
DOI:
10.1371/journal.pbio.3001455.g007
DOI:
10.1371/journal.pbio.3001455.g008
DOI:
10.1371/journal.pbio.3001455.s001
DOI:
10.1371/journal.pbio.3001455.s002
DOI:
10.1371/journal.pbio.3001455.s003
DOI:
10.1371/journal.pbio.3001455.s004
DOI:
10.1371/journal.pbio.3001455.s005
DOI:
10.1371/journal.pbio.3001455.s006
DOI:
10.1371/journal.pbio.3001455.s007
DOI:
10.1371/journal.pbio.3001455.s008
DOI:
10.1371/journal.pbio.3001455.s009
DOI:
10.1371/journal.pbio.3001455.s010
DOI:
10.1371/journal.pbio.3001455.s011
DOI:
10.1371/journal.pbio.3001455.s012
DOI:
10.1371/journal.pbio.3001455.s013
DOI:
10.1371/journal.pbio.3001455.s014
DOI:
10.1371/journal.pbio.3001455.r001
DOI:
10.1371/journal.pbio.3001455.r002
DOI:
10.1371/journal.pbio.3001455.r003
DOI:
10.1371/journal.pbio.3001455.r004
DOI:
10.1371/journal.pbio.3001455.r005
DOI:
10.1371/journal.pbio.3001455.r006
DOI:
10.1371/journal.pbio.3001455.r007
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X
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