PUBLICATION

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

Authors

Martínez-Morcillo, F.J., Cantón-Sandoval, J., Martínez-Navarro, F.J., Cabas, I., Martínez-Vicente, I., Armistead, J., Hatzold, J., López-Muñoz, A., Martínez-Menchón, T., Corbalán-Vélez, R., Lacal, J., Hammerschmidt, M., García-Borrón, J.C., García-Ayala, A., Cayuela, M.L., Pérez-Oliva, A.B., García-Moreno, D., Mulero, V.

ID

ZDB-PUB-211109-21

Date

2021

Source

PLoS Biology 19: e3001455 (Journal)

Registered Authors

Hammerschmidt, Matthias, Hatzold, Julia, Mulero, Victor

Keywords

none

MeSH Terms

Parthanatos*/drug effects
Parthanatos*/genetics
Keratinocytes/drug effects
Keratinocytes/metabolism
Keratinocytes/pathology
Poly(ADP-ribose) Polymerases/metabolism*
DNA Damage
Inflammation/genetics
Inflammation/pathology*
Reactive Oxygen Species/metabolism
Psoriasis/genetics
Psoriasis/pathology
Disease Models, Animal
Zebrafish
Skin/pathology*
NADPH Oxidases/antagonists & inhibitors
NADPH Oxidases/metabolism
Poly Adenosine Diphosphate Ribose/metabolism
Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
Cell Proliferation/drug effects
Zebrafish Proteins/deficiency
Zebrafish Proteins/metabolism
Gene Expression Regulation/drug effects
NAD/metabolism*
Apoptosis Inducing Factor/metabolism
Proteinase Inhibitory Proteins, Secretory/deficiency
Proteinase Inhibitory Proteins, Secretory/metabolism
Larva/metabolism
Oxidative Stress/drug effects
Oxidative Stress/genetics
Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors
Nicotinamide Phosphoribosyltransferase/metabolism*
Cell Nucleus/drug effects
Cell Nucleus/metabolism
Animals

(all 35)

PubMed

34748530 Full text @ PLoS Biol.

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.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
DsRed2	nz50Tg/nz50Tg	chemical treatment by environment: nicotinamide	Protruding-mouth	caudal hematopoietic tissue neutrophil	IFL	Fig 1
DsRed2	nz50Tg/nz50Tg	chemical treatment by environment: FK-866, chemical treatment by environment: NAD(+)	Protruding-mouth	caudal hematopoietic tissue neutrophil	IFL	Fig 1
DsRed2	nz50Tg/nz50Tg	chemical treatment by environment: nicotinamide mononucleotide	Protruding-mouth	caudal hematopoietic tissue neutrophil	IFL	Fig 1
DsRed2	nz50Tg/nz50Tg	chemical treatment by environment: FK-866	Protruding-mouth	caudal hematopoietic tissue neutrophil	IFL	Fig 1
DsRed2	nz50Tg/nz50Tg	chemical treatment by environment: NAD(+)	Protruding-mouth	caudal hematopoietic tissue neutrophil	IFL	Fig 1
EGFP	nc1Tg/nc1Tg	chemical treatment by environment: FK-866	Protruding-mouth	whole organism	IFL	Fig 1
EGFP	nc1Tg/nc1Tg	chemical treatment by environment: FK-866, chemical treatment by environment: NAD(+)	Protruding-mouth	whole organism	IFL	Fig 1
EGFP	nc1Tg/nc1Tg	chemical treatment by environment: NAD(+)	Protruding-mouth	whole organism	IFL	Fig 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment by environment: olaparib	Protruding-mouth	keratinocyte site of DNA damage ab7-h2afx labeling increased amount, abnormal	Fig 4
nc1Tg/nc1Tg	chemical treatment by environment: FK-866	Protruding-mouth	regulation of non-canonical NF-kappaB signal transduction increased process quality, abnormal	Fig 1
nc1Tg/nc1Tg	chemical treatment by environment: FK-866, chemical treatment by environment: NAD(+)	Protruding-mouth	regulation of non-canonical NF-kappaB signal transduction normal process quality, normal	Fig 1
nc1Tg/nc1Tg	chemical treatment by environment: NAD(+)	Protruding-mouth	regulation of non-canonical NF-kappaB signal transduction normal process quality, normal	Fig 1
nc1Tg/nc1Tg	chemical treatment by environment: NAD(+)	Protruding-mouth	whole organism EGFP expression increased amount, abnormal	Fig 1
nz50Tg/nz50Tg	standard conditions	Protruding-mouth	caudal fin regeneration normal process quality, normal	Fig 4
nz50Tg/nz50Tg	standard conditions	Protruding-mouth	keratinocyte DNA damage response normal process quality, normal	Fig 4
nz50Tg/nz50Tg	chemical treatment by environment: FK-866	Protruding-mouth	caudal hematopoietic tissue neutrophil DsRed2 expression increased amount, abnormal	Fig 1
nz50Tg/nz50Tg	chemical treatment by environment: FK-866	Protruding-mouth	caudal hematopoietic tissue neutrophil increased amount, abnormal	Fig 1
nz50Tg/nz50Tg	chemical treatment by environment: FK-866	Protruding-mouth	integument hydrogen peroxide biosynthetic process decreased occurrence, abnormal	Fig 1

1 - 10 of 58

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
hi2217Tg	Tg(nLacz-GTvirus)	Transgenic Insertion	spint1a
m14		Point Mutation	atp1b1a
nc1Tg	Tg(6xHsa.NFKB:EGFP)	Transgenic Insertion
nz50Tg	Tg(lyz:DsRed2)	Transgenic Insertion

1 - 4 of 4

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
aifm1	CRISPR1-aifm1	CRISPR
nampt1	CRISPR3-nampt1	CRISPR
nampt2	CRISPR4-nampt2	CRISPR
nox1	CRISPR3-nox1	CRISPR
nox4	CRISPR1-nox4	CRISPR
nox5	CRISPR4-nox5	CRISPR
parp1	CRISPR8-parp1	CRISPR

1 - 7 of 7

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Fish

Fish
AB
nc1Tg/nc1Tg
nz50Tg/nz50Tg
spint1a^{hi2217Tg/hi2217Tg}
spint1a^{hi2217Tg/hi2217Tg}; nc1Tg/nc1Tg
spint1a^{hi2217Tg/hi2217Tg}; nz50Tg/nz50Tg
spint1a^{hi2217Tg/hi2217Tg}; nz50Tg/nz50Tg + CRISPR1-aifm1
spint1a^{hi2217Tg/hi2217Tg}; nz50Tg/nz50Tg + CRISPR1-nox4
spint1a^{hi2217Tg/hi2217Tg}; nz50Tg/nz50Tg + CRISPR3-nox1
spint1a^{hi2217Tg/hi2217Tg}; nz50Tg/nz50Tg + CRISPR4-nox5

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Antibodies

Name	Type	Isotypes	Host Organism
Ab1-casp3	monoclonal	IgG	Rabbit
Ab3-aifm1p1	polyclonal	IgG	Rabbit
Ab7-h2afx	polyclonal	IgG	Rabbit

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed2	EFG	DsRed2
EGFP	EFG	EGFP

Mapping

Martínez-Morcillo et al., 2021 ZDB-PUB-211109-21 PMID:34748530

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

Martínez-Morcillo et al., 2021

ZDB-PUB-211109-21
PMID:34748530