NAD⁺ Augmentation by Nicotinamide Riboside Engages SLIT2/ROBO1 Signaling to Attenuate Th17 Inflammation in Psoriasis

BACKGROUND. Enhancing NAD+ level by Nicotinamide Riboside (NR) supplementation confer anti-inflammatory effects in human disease, yet the immunoregulatory mechanisms remain unclear. We previously demonstrated ex vivo study that NR blunts CD4+ T cell immune responsiveness in psoriasis. To explore whether these effects occur in vivo, we conducted a randomized, placebo-controlled NR supplementation study in participants with mild-tomoderate- psoriasis. METHODS. Psoriasis participants consumed oral NR supplementation (500 mg twice daily) or matching placebo for 4 weeks. Research bloods were drawn at baseline and at 4 weeks for analysis. In parallel, natural history cohorts of healthy controls and psoriasis participants donated research blood and skin punch biopsies for mechanistic analysis. RESULTS. Oral NR supplementation dampens Th17 immune responsiveness. Bulk RNA-seq of CD4+ cells identified that NR regulated the SLIT-ROBO signaling pathway. Participants on NR showed elevated circulating SLIT2 levels, and NR increased SLIT2 production in skin fibroblasts. Pharmacologic and genetic studies in CD4+ T cells and fibroblasts showed that SLIT2, acting through the ROBO1 receptor, inhibited Rho GTPase signaling, thereby reducing canonical Th17 polarization and fibroblast inflammatory activation. CONCLUSION. NAD+ augmentation confers anti-inflammatory effects in psoriasis through SLIT2/ROBO1-mediated crosstalk between dermal fibroblast and circulating CD4+ T cells, leading to attenuation of Th17-driven inflammation.