Role of Lgals9 Deficiency in Attenuating Nephritis and Arthritis in BALB/c Mice in a Pristane-Induced Lupus Model

Objective: In systemic lupus erythematosus (SLE), an autoimmune disease associated with multiple organ involvement, the development of lupus nephritis determines prognosis, and arthritis impairs quality of life. Galectin 9 (Gal-9, Lgals9) is a β-galactoside–binding lectin that has been used for clinical application in autoimmune diseases, since recombinant Gal-9, as a ligand for T cell immunoglobulin and mucin domain–containing protein 3 (TIM-3), induces apoptosis of activated CD4+TIM-3+ Th1 cells. This study was undertaken to investigate whether deficiency of Lgals9 has beneficial or deleterious effects on lupus in a murine model. Methods: Gal-9^+/+ and Gal-9^−/− female BALB/c mice were injected with pristane, and the severity of arthritis, proteinuria, and levels of autoantibody production were assessed at several time points immediately following injection. At 7 months after pristane injection, renal pathologic features, the severity of joint inflammation, and formation of lipogranulomas were evaluated. Subsets of inflammatory cells in the spleen and peritoneal lavage were characterized, and expression levels of cytokines from peritoneal macrophages were analyzed. Results: Lgals9 deficiency protected against the development of immune complex glomerulonephritis, arthritis, and peritoneal lipogranuloma formation in BALB/c mice in this murine model of pristane-induced lupus. The populations of T cell subsets and B cells in the spleen and peritoneum were not altered by Lgals9 deficiency in pristane-injected BALB/c mice. Furthermore, Lgals9 deficiency protected against pristane-induced lupus without altering the Toll-like receptor 7–type I interferon pathway. Conclusion: Gal-9 is required for the induction and development of lupus nephritis and arthritis in this murine model of SLE. The results of the current investigation provide a potential new strategy in which antagonism of Gal-9 may be beneficial for the treatment of nephritis and arthritis in patients with SLE through targeting of activated macrophages.