Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China; Department of General Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China; National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
Eur J Pharmacol. 2024 Aug 15;977:176703. doi: 10.1016/j.ejphar.2024.176703. Epub 2024 Jun 3.
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 that participates in regulating multiple signaling pathways. Inhibition of PP2A has been implicated in the treatment of various diseases. LB-100, a small molecule inhibitor of PP2A, has demonstrated anti-tumor therapeutic effects and high safety profile in preclinical experiments. 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 both spontaneous and R848-induced lupus mouse models. Importantly, we observed the formation of tertiary lymphoid structures (TLSs) in the kidneys of two distinct lupus mouse models. The levels of signature genes of TLS were elevated in the kidneys of lupus mice, whereas LB-100 mitigated chemokine production and inhibited TLS formation. In addition, we confirmed that inhibition or knockdown of PP2A reduced the production of T cell-related chemokines by renal tubular epithelial cells (RTEC). In summary, our study 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 treating LN and other autoimmune diseases.
系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征为多器官受累和自身抗体产生。SLE 患者面临发生狼疮性肾炎（LN）的高风险，这给患者及其家庭带来了沉重的负担。蛋白磷酸酶 2A（PP2A）是一种广泛分布的丝氨酸/苏氨酸磷酸酶，参与调节多种信号通路。抑制 PP2A 已被认为可用于治疗多种疾病。LB-100 是一种 PP2A 的小分子抑制剂，在临床前实验中已显示出抗肿瘤治疗效果和高安全性。然而，PP2A 及其抑制剂在 LN 中的作用尚未得到充分研究。在本研究中，我们评估了 LB-100 在 MRL/lpr 小鼠和 R848 诱导的 BALB/c 小鼠中的潜在作用。我们的研究结果表明，LB-100 给药可导致自发性和 R848 诱导的狼疮小鼠模型的脾脏肿大减轻、免疫复合物沉积减少、肾脏损伤改善和肾功能改善。重要的是，我们观察到在两种不同的狼疮小鼠模型的肾脏中形成了三级淋巴样结构（TLSs）。狼疮小鼠肾脏中 TLS 的特征基因水平升高，而 LB-100 可减轻趋化因子的产生并抑制 TLS 的形成。此外，我们证实抑制或敲低 PP2A 可减少肾小管上皮细胞（RTEC）产生与 T 细胞相关的趋化因子。综上所述，我们的研究强调了 PP2A 抑制剂 LB-100 在两种不同狼疮小鼠模型中的肾脏保护潜力，表明其可能成为治疗 LN 和其他自身免疫性疾病的新策略。
