Inhibition of STING modulates dendritic cell responses and ameliorates podocyte injury in SLE.

Abstract

Background: SLE features aberrant type I interferon production, with the stimulator of interferon genes (STING) pathway acting as a key upstream driver. However, its expression patterns in patients with SLE and contributions to clinical phenotypes and tissue injury remain insufficiently defined.

Methods: The proportion of STING-positive cells in peripheral blood mononuclear cells (PBMCs) from 28 patients with SLE and 15 healthy controls was analysed alongside clinical and serological features. Glomerular STING expression and podocyte injury were assessed in kidney biopsies from 39 patients with lupus nephritis (LN) and circulating and renal STING expression was compared in a paired cohort. The therapeutic effects of STING inhibitor C176 were evaluated in MRL/lpr mice by examining kidney pathology, proteinuria, function, immune cell subsets and podocyte injury. STING-mediated regulation of dendritic cell (DC) activation and plasmacytoid DC (pDC) differentiation was further investigated in vivo and in vitro.

Results: STING expression was significantly elevated in PBMCs from patients with SLE and kidney tissues from patients with LN, particularly in proliferative LN and correlated with glomerular proliferation and decreased synaptopodin expression, suggesting an association with podocyte injury. STING activation promoted DC activation and pDC differentiation. Furthermore, conditioned media from STING-activated DCs induced podocyte apoptosis and reduced synaptopodin expression, effects attenuated by STING inhibition, indicating that STING activation in DCs promotes podocyte injury and disrupts podocyte homeostasis in a paracrine manner. C176 treatment in MRL/lpr mice significantly alleviated splenomegaly, proteinuria, kidney inflammation and renal dysfunction, while restoring podocyte integrity and reshaping immune responses.

Conclusion: Our findings suggest a potential role for STING in the interplay between immune dysregulation and podocyte injury in lupus. Pharmacological STING inhibition modulates DC responses and partially protects podocytes and renal structure, supporting STING as a promising therapeutic target for SLE.