Gluconolactone restores immune regulation and alleviates skin inflammation in lupus-prone mice and in patients with cutaneous lupus

Systemic lupus erythematosus (SLE) is characterized by dysfunctional regulatory T cells (T regs ). We previously showed that protein phosphatase 2A (PP2A) plays a critical role in maintaining the suppressive function of T regs . Here, we analyzed phosphoproteomics and metabolomics data from PP2A–wild type and PP2A-deficient T regs and demonstrated that PP2A regulates T reg function through the pentose phosphate pathway (PPP). Furthermore, we proved that the PPP metabolite gluconolactone (GDL) enhances in vitro induced (i)T reg differentiation and function by promoting forkhead box protein 3 and phosphorylated signal transducer and activator of transcription 5 expression and inhibits T helper 17 (T H 17) differentiation in murine cells. In short-term imiquimod-induced autoimmunity in mice, treatment with GDL alleviates inflammation by inhibiting T H 17 cells. GDL promotes T regs function and alleviates skin lesions in MRL. lpr lupus-prone mice in vivo. It also promotes T regs differentiation and function in ex vivo experiments using cells from patients with SLE. Last, in patients suffering from cutaneous lupus erythematosus, topical application of a GDL-containing cream controlled skin inflammation and improved the clinical and histologic appearance of the skin lesions within 2 weeks. Together, we have identified GDL as a PPP metabolite and showed mechanistically that it restores immune regulation in vitro and in vivo by inducing T reg suppressive function and inhibiting T H 17 cells. GDL should be considered as a treatment approach for inflammatory and autoimmune diseases.