# Epidermal NAD+ deficiency induces IL-36–mediated skin inflammation and acanthosis

## TL;DR

Low NAD+ in the skin causes inflammation and thickening, which could lead to new treatments for skin diseases.

## Contribution

This study reveals a novel link between NAD+ deficiency and IL-36–mediated skin inflammation in mice.

## Key findings

- NAD+ deficiency in the epidermis causes PARP inactivation and DNA damage.
- IL-36 levels rise due to genomic stress, promoting skin inflammation and hyperplasia.
- NAD+ repletion with NMN reduces IL-36 and inflammation.

## Abstract

Nicotinamide adenine dinucleotide (NAD+) is essential for cellular metabolism, DNA repair, and stress responses. NAD+ is synthesized from nicotinamide, nicotinic acid (collectively termed niacin), and tryptophan. In humans, deficiencies in these nutrients result in pellagra, marked by dermatitis, diarrhea, and dementia. The dermatitis associated with pellagra typically manifests as photodermatosis in sun-exposed areas. This study examined the effects of NAD+ deficiency on skin homeostasis using epidermis-specific Nampt–conditional KO (Nampt-cKO) mice. These mice displayed substantial NAD+ depletion, reduced poly(ADP-ribose) polymerase (PARP) activity, and increased DNA damage. Consequently, Nampt-cKO mice developed spontaneous skin inflammation and epidermal hyperplasia. RNA-seq and IHC analyses demonstrated increased IL-36 cytokine expression, suggesting that DNA repair–related genomic stress triggers keratinocyte-driven IL-36 production, which promotes inflammation. Furthermore, reduced COL17A1 expression and elevated thymic stromal lymphopoietin (TSLP) levels were observed. NAD+ repletion by transdermal supplementation of nicotinamide mononucleotide (NMN) suppressed the rise of IL-36 levels and skin inflammation. These findings underscore the importance of Nampt-mediated NAD+ metabolism for epidermal stability and indicate that NAD+ depletion may contribute to IL-36–mediated skin inflammation, offering insights for therapeutic strategies in inflammatory skin disorders.

Epidermal loss of Nampt causes a marked reduction in NAD+ levels, PARP inactivation, and increased DNA damage, leading to spontaneous skin inflammation and keratinocyte hyperproliferation.