Single-Cell RNA sequencing identifies NAMPT as a potential therapeutic target in autoimmune uveitis

Le résumé fourni par la source

• Inhibition of NAMPT significantly ameliorates both the clinical symptoms and histopathological features of EAU. • NAMPT inhibition reverses abnormal, disease-associated transcriptional programs within immune cell populations in EAU, particularly in CD4 + T cells. • Suppressing NAMPT reduces Th17 and Th1 responses while enhancing Treg populations. • NAMPT inhibition restores the Teff/Treg balance by downregulating Hif1α. • NAMPT expression is elevated in CD4 + T cells from patients with uveitis. • A conserved NAMPT-Hif1α signaling axis exists in human uveitis. Autoimmune uveitis (AU) is an autoimmune disease of the eye that can lead to irreversible vision loss. Current therapies are limited by suboptimal efficacy and substantial side effects, highlighting the urgent need for the discovery of novel therapeutic targets. Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme controlling the NAD + salvage pathway and also exerts immunoregulatory and anti-inflammatory effects. However, its role in AU remains unclear. To investigate NAMPT’s effects on AU and underlying mechanisms. Single-cell RNA sequencing (scRNA-seq) was performed on cervical draining lymph node (CDLN) cells from normal, experimental autoimmune uveitis (EAU), and NAMPT inhibitor-treated EAU mice. The influence of NAMPT inhibition on immune cell subsets, transcriptional programs, and intercellular communication networks was comprehensively analyzed. Additionally, scRNA-seq was performed on peripheral blood mononuclear cells (PBMCs) collected from Vogt-Koyanagi-Harada (VKH) disease patients and healthy controls (HC) to assess NAMPT expression and its modulation in human CD4 + T cells. In vivo and in vitro experiments, flow cytometry, and adoptive transfer experiments confirmed NAMPT’s role in uveitis. NAMPT inhibition significantly ameliorated the clinical and histopathological manifestations of EAU. scRNA-seq revealed that NAMPT blockade reshaped immune cell composition and reversed disease-associated transcriptional programs, particularly within CD4 + T cells. It suppressed pro-inflammatory T helper (Th)-17 and Th1 responses while promoting regulatory T cell (Treg) populations. Mechanistically, NAMPT inhibition modulated the Th17/Treg balance by downregulation of Hif1α expression. In VKH patients, CD4 + T cells exhibited elevated NAMPT expression, which led to increased Th17 and Th1 cells and reduced Tregs. NAMPT knockdown reproduced the protective phenotype observed with FK866 treatment, suggesting a conserved NAMPT-Hif1α axis in human uveitis. Inhibiting NAMPT can reverse the imbalance of effector T (Teff)/Treg cells by suppressing the expression of Hif1α in CD4 + T cells, thereby effectively alleviating the symptoms of EAU. Therefore, NAMPT might be a potential target for AU.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.