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

Abstract

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. HighlightsO_LINAMPT inhibition alleviates inflammation in zebrafish and human epidermis organoid models of psoriasis. C_LIO_LINADPH oxidase-derived ROS mediates keratinocyte DNA damage and Parp1 overactivation. C_LIO_LIInhibition of parthanatos cell death phenocopies the effects of NAMPT inhibition in zebrafish and human psoriasis models. C_LIO_LINAMPT and PAR metabolism is altered in psoriasis patients. C_LI