Division of Immunology, Department of Biology, University of Konstanz, 78457 Konstanz, Germany; and
Biotechnology Institute Thurgau at the University of Konstanz, 8280 Kreuzlingen, Switzerland.
J Immunol. 2019 Oct 1;203(7):1776-1785. doi: 10.4049/jimmunol.1900182. Epub 2019 Sep 4.
MECL-1 (β2i), LMP2 (β1i), and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome (IP), a special type of proteasome mainly expressed in hematopoietic cells. Targeting the IP in autoimmune diseases proved to be therapeutically effective in preclinical mouse models. In endotoxin-stimulated human PBMCs, IP inhibition reduces the secretion of several proinflammatory cytokines, with the suppression of IL-23 being the most prominent. In this study, we investigated why the production of IL-23, a key mediator of inflammation in autoimmunity, is blocked when the IP is inhibited in LPS-stimulated human PBMCs. CD14 monocytes could be identified as the main producers of IL-23 in LPS-stimulated PBMCs. We found that IP inhibition with the irreversible LMP7/LMP2 inhibitor ONX 0914 induced apoptosis in CD14 monocytes, whereas CD4, CD3, CD19, and CD56 cells remained unaffected. A high expression of IPs renders monocytes susceptible to IP inhibition, leading to an accumulation of polyubiquitylated proteins and the induction of the unfolded protein response. Similar to IP inhibition, inducers of the unfolded protein response selectively kill CD14 monocytes in human PBMCs. The blockage of the translation in CD14 monocytes protects these cells from ONX 0914-induced cell death, indicating that the IP is required to maintain protein turnover in monocytes. Taken together, our data reveal why IP inhibition is particularly effective in the suppression of IL-23-driven autoimmunity.
MECL-1（β2i）、LMP2（β1i）和 LMP7（β5i）是免疫蛋白酶体（IP）的蛋白水解活性亚基，免疫蛋白酶体是一种主要在造血细胞中表达的特殊蛋白酶体。在自身免疫性疾病的临床前小鼠模型中，靶向免疫蛋白酶体被证明具有治疗效果。在脂多糖刺激的人 PBMC 中，免疫蛋白酶体抑制可减少几种促炎细胞因子的分泌，其中对 IL-23 的抑制最为明显。在这项研究中，我们研究了为什么在脂多糖刺激的人 PBMC 中抑制免疫蛋白酶体时，会阻断 IL-23 的产生，而 IL-23 是自身免疫炎症的关键介质。CD14 单核细胞可被鉴定为脂多糖刺激的 PBMC 中 IL-23 的主要产生细胞。我们发现，不可逆的 LMP7/LMP2 抑制剂 ONX 0914 抑制免疫蛋白酶体可诱导 CD14 单核细胞凋亡，而 CD4、CD3、CD19 和 CD56 细胞不受影响。高表达免疫蛋白酶体使单核细胞易受免疫蛋白酶体抑制，导致多泛素化蛋白积累并诱导未折叠蛋白反应。与免疫蛋白酶体抑制类似，未折叠蛋白反应的诱导剂可选择性杀死人 PBMC 中的 CD14 单核细胞。CD14 单核细胞中的翻译阻断可保护这些细胞免受 ONX 0914 诱导的细胞死亡，表明免疫蛋白酶体需要维持单核细胞中的蛋白质周转。总之，我们的数据揭示了为什么免疫蛋白酶体抑制在抑制 IL-23 驱动的自身免疫中特别有效。
