NAD+ augmentation by nicotinamide riboside engages SLIT2/ROBO1 signaling to attenuate Th17 inflammation in psoriasis

BACKGROUNDEnhancing NAD+ levels with nicotinamide riboside (NR) confers antiinflammatory effects in human disease, although immunoregulatory mechanisms remain poorly characterized. We previously showed that ex vivo NR supplementation of primary CD4+ T cells from psoriatic individuals dampened immune responsiveness.METHODSTo validate this in vivo, we performed a randomized, placebo-controlled NR supplementation study in individuals with mild-to-moderate psoriasis. Participants received oral NR (500 mg twice daily) or matching placebo for 4 weeks, with blood samples collected at baseline and after supplementation. NR reduced Th17 immune responsiveness.RESULTSBulk CD4+ T cell RNA-seq identified induction of the SLIT-ROBO signaling pathway. NR supplementation increased circulating SLIT2 levels and enhanced SLIT2 production in dermal fibroblasts. Pharmacologic and genetic interrogation in CD4+ T cells and fibroblasts demonstrated that SLIT2, acting through the ROBO1 receptor, inhibited Rho GTPase signaling, thereby attenuating canonical Th17 polarization and fibroblast inflammatory activation.CONCLUSIONThese findings indicate that NAD+ augmentation exerts anti-inflammatory effects in psoriasis through SLIT2-ROBO1-mediated crosstalk between dermal fibroblasts and circulating CD4+ T cells, leading to suppression of Th17-driven inflammation.TRIAL REGISTRATIONClinicalTrials.gov NCT04271735 (registration date - 2020-08026), NCT01143454 (registration date - 2010-07-21), NCT01778569 (registration date - 2013-01-22), and NCT00001846 (registration date - 2001-01-11).FUNDINGThe NHLBI Division of Intramural Research (HL005102 - MNS).