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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 knockout (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 sequencing and immunohistochemical analyses demonstrated increased interleukin-36 (IL-36) cytokine expression, suggesting that DNA repair-related genomic stress triggers keratinocyte-driven IL-36 production, which promotes inflammation. Furthermore, reduced collagen17A1 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.
Authors
Taiki Seki, Jun-Dal Kim, Yasuhito Yahara, Hitoshi Uchida, Keisuke Yaku, Mariam Karim, Teruhiko Makino, Tadamichi Shimizu, Takashi Nakagawa
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