Podocyte Interleukin-23 Receptor Signaling in the Pathogenesis of Lupus Nephritis.

Abstract

Up-regulation of interleukin-23 (IL-23) in the serum and kidneys of patients with lupus nephritis (LN) has been demonstrated, but its effect on podocytes remains unknown. We hypothesized that IL-23 contributes to podocyte injury and that targeted deletion of IL-23 receptor (IL-23R) in podocytes of lupus-prone mice can prevent the development of glomerulonephritis. Kidney biopsies were immunostained for IL-23R. In vitro experiments were conducted using a human podocyte cell line and primary murine podocytes. Human podocytes stimulated with IL-23 underwent bulk RNA sequencing. The expression of IL-23R and structure and motility of podocytes were assessed. Podocytes isolated from B6 wild-type mice injected with a minicircle (MC) encoding IL-23 were studied. To assess the role of IL-23R in the development of nephritis, we generated MRL/lpr mice deficient in podocyte-specific Il23r who were lupus prone. IL-23R was highly expressed in the glomeruli of patients with LN. IL-23R expression was also up-regulated in human podocytes and primary podocytes isolated from B6 mice after IL-23 stimulation. Human podocytes stimulated with IL-23 showed decreased expression of synaptopodin and remodeling of the actin cytoskeleton. Mice who were administered with IL-23 MC mice exhibited a significant increase in the expression of IL-23R and phosphorylated STAT3 in podocytes. Finally, MRL/lpr.Podo-Cre⁺ Il23r^fl/fl mice showed decreased clinical and histologic features of LN. IL-23R expression is increased in podocytes from mice and humans with systemic lupus erythematosus. IL-23 signaling disrupts the cytoskeleton in podocytes and increases their mobility, leading to the development of glomerulonephritis. Podocyte-specific deletion of Il23r in lupus-prone mice abrogates the development of LN.