IL-18 Promotes the Development of Lupus Nephritis by Activating the Wnt/β-Catenin Signaling Pathway in Renal Tubular...

This study investigates the specific role of interleukin-18 (IL-18) in lupus nephritis (LN) progression and its molecular mechanisms to provide a theoretical basis for the pathological intervention of LN. IL-18 levels were measured from systemic lupus erythematosus (SLE) patients with or without LN. MRL/lpr mice received intraperitoneal injection of IL-18 or its inhibitor to assess renal injury, inflammation, and Wnt/β-catenin pathway activity. In-vivo intervention experiments using Caspase-1 inhibitor (Ac-YVAD-CMK), Wnt pathway agonists (BML-284), and inhibitors (IWR-1-endo) were performed. In-vitro studies were conducted in human renal tubular epithelial cell line HK-2 to investigate the molecular mechanisms. IL-18 was markedly elevated in SLE patients, and further increased in urine and renal tissue of LN. In MRL/lpr mice, exogenous IL-18 significantly exacerbated renal injury, evidenced by increased urinary protein, serum creatinine, anti-dsDNA antibodies, tubulointerstitial inflammation, and increased activity index. This was accompanied by up-regulation of IFN-γ, IL-1β, IL-6, down-regulation of IL-10, and activation of the Wnt/β-catenin pathway (increased β-catenin, p-GSK-3β, and CK1α). Conversely, IL-18 blockade or Wnt inhibition attenuated these pathological changes. Notably, the protective effects of IL-18 inhibition were reversed by simultaneous Wnt activation. In-vitro, IL-18 promoted HK-2 cell proliferation and inflammatory secretion by activating Wnt/β-catenin signaling, effects which were blocked by a Caspase-1 inhibitor or a Wnt pathway inhibitor. IL-18 activated the Wnt/β-catenin signaling pathway in renal tubular epithelial cells and disrupted the balance of pro- and anti-inflammatory cytokine networks, thereby exacerbating tubulointerstitial inflammation and promoting renal injury in LN mice. These findings highlight the therapeutic potential of targeting the IL-18 signaling pathway in LN. Trial registration: Not applicable.