Gluconolactone restores immune regulation and alleviates skin inflammation in lupus-prone mice and in patients with cutaneous lupus 2328666

Abstract

Abstract Introduction Systemic lupus erythematosus (SLE) is characterized by impaired regulatory T cell (Treg) function and dysregulated immune metabolism. We previously identified protein phosphatase 2A (PP2A) as a critical regulator of Treg suppressive activity. Emerging evidence suggests that the pentose phosphate pathway (PPP) plays an essential role in immune cell fate decisions. Methods Phosphoproteomic and metabolomic analyses were performed on Treg cells from PP2A—wild-type and PP2A-deficient mice. The PPP metabolite gluconolactone (GDL) was evaluated for its effects on CD4+ T cell differentiation and Treg suppressive function in murine and human cells in vitro. The therapeutic efficacy of GDL was assessed in vivo using imiquimod-induced dermatitis and spontaneous lupus-prone MRL.lpr mouse models. Finally, the clinical and histologic effects of topical GDL were evaluated in a pilot study of patients with cutaneous lupus erythematosus. Results PP2A regulates Treg function through modulation of the PPP. We identified GDL as a key PPP metabolite that enhances induced Treg differentiation and suppressive function while inhibiting T helper 17 (TH17) cell differentiation in murine T cells. In vivo, GDL treatment increased Treg function and significantly ameliorated skin inflammation in both imiquimod-induced and spontaneous lupus mouse models. Ex vivo studies using T cells from patients with SLE demonstrated that GDL similarly promoted Treg differentiation and function. Notably, topical application of a GDL-containing cream in patients with cutaneous lupus erythematosus led to marked clinical and histologic improvement of skin lesions within two weeks Conclusion Our findings identify gluconolactone as a metabolite of the pentose phosphate pathway that restores immune regulation by enhancing Treg function and suppressing TH17 responses. GDL represents a promising metabolic-based therapeutic strategy for the treatment of inflammatory and autoimmune diseases. Funding Source NIH Topic Categories Immune Mechanisms of Human Disease (HUM)