Epidermal NAD+ deficiency induces IL-36–mediated skin inflammation and acanthosis
Taiki Seki, Jun-Dal Kim, Yasuhito Yahara, Hitoshi Uchida, Keisuke Yaku, Mariam Karim, Teruhiko Makino, Tadamichi Shimizu, Takashi Nakagawa
Taiki Seki, Jun-Dal Kim, Yasuhito Yahara, Hitoshi Uchida, Keisuke Yaku, Mariam Karim, Teruhiko Makino, Tadamichi Shimizu, Takashi Nakagawa
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Research Article Dermatology Metabolism

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

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.

Authors

Taiki Seki, Jun-Dal Kim, Yasuhito Yahara, Hitoshi Uchida, Keisuke Yaku, Mariam Karim, Teruhiko Makino, Tadamichi Shimizu, Takashi Nakagawa

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Figure 5

Topical NMN treatment ameliorates skin inflammation in Nampt-cKO mice.

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Topical NMN treatment ameliorates skin inflammation in Nampt-cKO mice. (...
(A) Experimental time line showing tamoxifen administration, topical NMN treatment, and sample collection for control and Nampt-cKO mice. (B) NAD+ levels in the epidermis of control and Nampt-cKO mice with NMN or saline treatment on Day 19, as measured by LC/MS. Data are shown as mean ± SEM. Two-way ANOVA with Tukey’s post hoc test. n = 6. (C) Nampt mRNA levels in epidermis of control and Nampt-cKO mice with NMN or saline treatment on Day 19, as determined by qPCR. Data are shown as mean ± SEM. Two-way ANOVA with Tukey’s post hoc test. n = 6. (D) Representative clinical photographs of control and Nampt-cKO mice with NMN or saline treatment on Day 19. (E) Representative H&E-stained sections of control and Nampt-cKO mice with NMN or saline treatment on Day 19. Scale bars: 100 μm. (F and G) Gene expression levels of inflammation-related cytokines in epidermis of control and Nampt-cKO mice with NMN or saline treatment on Day 19, as determined by qPCR. Data are shown as mean ± SEM. Two-way ANOVA with Tukey’s post hoc test. n = 6. (H) Representative IHC images for IL-36A in the epidermis of control and Nampt-cKO mice with NMN or saline treatment on Day 19. Hematoxylin was used for counterstain. Scale bars: 100 μm. (I) Quantification of IL-36A in immunofluorescence images using ImageJ. Data are shown as mean ± SEM. Two-way ANOVA with Tukey’s post hoc test. n = 6. (J) Western blot analysis for IL-36A in the epidermis of control and Nampt-cKO mice with NMN or saline treatment on Day 19. Pan-actin was used as a loading control. (K) Semiquantitative densitometric analysis of IL-36A Western blots normalized to pan-actin using ImageJ. Data are shown as mean ± SEM. Two-way ANOVA with Tukey’s post hoc test. n = 3. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.