Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells.
Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells.
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DOI：
10.1002/art.33333
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发表时间：
2012-02
影响因子：
--
通讯作者：
Anolik JH
中科院分区：
文献类型：
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作者：
Ichikawa HT;Conley T;Muchamuel T;Jiang J;Lee S;Owen T;Barnard J;Nevarez S;Goldman BI;Kirk CJ;Looney RJ;Anolik JH
我们推测，蛋白酶体抑制（PI）可能通过靶向浆细胞样树突状细胞（pDC）和浆细胞（PC）来治疗系统性红斑狼疮，这两种细胞对疾病发病机制都至关重要。患有狼疮的小鼠接受非选择性 PI 卡非佐米和硼替佐米、LMP7 选择性免疫蛋白酶体抑制剂 ONX 0914 或载体对照治疗。收获组织并使用标准标记物通过流式细胞术进行分析。通过蛋白尿和肾脏采集来监测肾炎。通过 ELISA 测量血清抗 dsDNA 水平，通过 ELIspot 测量总 IgG 和 dsDNA 抗体分泌细胞 (ASC)。将人 PBMC 或小鼠骨髓细胞与 TLR 激动剂和 PI 以及通过 ELISA 和流式细胞术测量的干扰素 α 一起孵育。用双重靶向PI卡非佐米或硼替佐米或免疫蛋白酶体特异性抑制剂ONX 0914对易患狼疮的小鼠进行早期治疗可防止疾病进展，而对患有已确定疾病的小鼠进行治疗可显着消除肾炎。治疗对浆细胞产生了深远的影响，与总 IgG ASC 相比，其自身反应性降低幅度更大，这种效果随着治疗时间的延长而变得更加明显，并反映在血清自身抗体的降低上。值得注意的是，蛋白酶体抑制可在体外和体内有效抑制 Toll 样受体激活的 pDC 产生干扰素 α，这是通过抑制 pDC 存活和功能介导的效应。通过靶向疾病发病机制中的两个关键途径（I 型干扰素激活和浆细胞产生自身抗体），免疫蛋白酶体的抑制与双靶向药物在预防狼疮疾病进展方面同样有效。
We postulated that proteasome inhibition (PI) may be useful in the treatment of SLE by targeting plasmacytoid dendritic cells (pDCs) and plasma cells (PCs), both critical to disease pathogenesis. Lupus prone mice were treated with the non-selective PIs carfilzomib and bortezomib, the LMP7-selective immunoproteasome inhibitor ONX 0914, or vehicle control. Tissues were harvested and analyzed by flow cytometry using standard markers. Nephritis was monitored by proteinuria and kidney harvest. Serum anti-dsDNA levels were measured by ELISA and total IgG and dsDNA antibody secreting cells (ASC) by ELIspot. Human PBMCs or mouse bone marrow cells were incubated with TLR agonists and PIs and interferon α measured by ELISA and flow cytometry. Early treatment of lupus prone mice with the dual targeting PIs carfilzomib or bortezomib or the immunoproteasome specific inhibitor ONX 0914 prevented disease progression, and treatment of mice with established disease dramatically abrogated nephritis. Treatment had profound effects on plasma cells with greater reductions in autoreactive than total IgG ASCs, an effect that became more pronounced with prolonged treatment, and was reflected in decreasing serum autoantibodies. Remarkably, proteasome inhibition efficiently suppressed production of interferon α by toll-like receptor activated pDCs in vitro and in vivo, an effect mediated by both an inhibition of pDC survival and function. Inhibition of the immunoproteasome is equally efficacious to dual targeting agents in preventing lupus disease progression by targeting two critical pathways in disease pathogenesis, type I interferon activation and autoantibody production by plasma cells.