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_H17) differentiation in murine cells. In short-term imiquimod-induced autoimmunity in mice, treatment with GDL alleviates inflammation by inhibiting T_H17 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_H17 cells. GDL should be considered as a treatment approach for inflammatory and autoimmune diseases.