The PP2A inhibitor LB-100 mitigates lupus nephritis by suppressing tertiary lymphoid structure formation

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ involvement and autoantibody production. Patients with SLE face a substantial risk of developing lupus nephritis (LN), which imposes a substantial burden on both patients and their families. Protein phosphatase 2A (PP2A) is a widely distributed serine/threonine phosphatase participated in regulating multiple signaling pathways and immune responses. Inhibition of PP2A is implicated in the treatment of diseases. LB-100, a small molecule inhibitor of PP2A, is currently undergoing preclinical trials for its therapeutic potential against tumors. However, the role of PP2A and its inhibitor has been insufficiently studied in LN. In this study, we assessed the potential effects of LB-100 in both MRL/lpr mice and R848-induced BALB/c mice. Our findings indicated that LB-100 administration led to reduced spleen enlargement, decreased deposition of immune complexes, ameliorated renal damage, and improved kidney function in two distinct lupus mouse models. Importantly, we observed the formation of tertiary lymphoid structures (TLS) in the kidneys of both spontaneous and induced lupus mouse models. The levels of chemokines inducing T cell infiltration were elevated in the kidneys of lupus mice, whereas LB-100 mitigated chemokines production and inhibited TLS formation. In summary, our study identified the role of PP2A in LN and highlighted the renal protective potential of the PP2A inhibitor LB-100 in two distinct lupus mouse models, suggesting its potential as a novel strategy for LN and other autoimmune diseases.