Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjogren's syndrome
Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjogren's syndrome
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蛋白酶体抑制可抑制 Th17 细胞生成并改善实验性干燥综合征的自身免疫发展
DOI：
10.1038/cmi.2017.8
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发表时间：
2017-11-01
影响因子：
24.1
通讯作者：
Lu, Liwei
中科院分区：
文献类型：
--
作者：
Xiao, Fan;Lin, Xiang;Lu, Liwei
免疫细胞中的免疫蛋白酶体活化参与了免疫反应的调节。越来越多的证据表明，蛋白酶体抑制剂在治疗自身免疫性疾病方面显示出有益的效果，但目前尚不清楚蛋白酶体抑制是否是抑制干燥综合征（SS）自身免疫性发展的有效途径。我们之前的工作已经证明Th17细胞在小鼠实验性SS （ESS）的发展中起着关键作用。在这项研究中，我们在ESS小鼠的Th17细胞中检测到高水平的低分子量蛋白7 (LMP7)，这是免疫蛋白酶体的一个关键亚基。此外，硼替佐米（BTZ）是一种蛋白酶体抑制剂，在培养的小鼠和人初始T细胞中显著抑制Th17的分化。此外，与小鼠对照组相比，BTZ治疗的ESS小鼠表现出更高的唾液流率和更少的唾液腺组织破坏。值得注意的是，btz处理的ESS小鼠外周血淋巴器官中Th17细胞、生发中心B细胞和浆细胞明显减少。此外，过继转移的野生型初始CD4(+) T细胞迅速分化为Th17细胞，并在免疫ESS诱导的il -17缺陷小鼠中诱导唾液功能障碍。然而，BTZ治疗深刻地抑制了供体t细胞来源的Th17反应，改善了il -17缺陷受体小鼠唾液分泌的减少。综上所述，我们的研究结果表明，蛋白酶体抑制可以通过抑制Th17反应有效地改善ESS，这可能有助于开发一种新的治疗SS的治疗策略。
Immunoproteasome activation in immune cells is involved in the modulation of immune responses. Increasing evidence indicates that proteasome inhibitors show beneficial effects in treating autoimmune diseases, but it remains unclear whether proteasome inhibition is an effective approach for suppressing autoimmune development in Sjogren's syndrome (SS). Our previous work has demonstrated a critical role for Th17 cells in the development of experimental SS (ESS) in mice. In this study, we detected high levels of low-molecular-weight protein 7 (LMP7), a key subunit of the immunoproteasome, in Th17 cells from ESS mice. Moreover, treatment with bortezomib (BTZ), a proteasome inhibitor, markedly suppressed Th17 differentiation in both murine and human naive T cells in culture. Furthermore, ESS mice treated with BTZ displayed significantly higher saliva flow rates and a reduction in tissue destruction in the salivary glands compared with vehicle-treated ESS mice. Notably, BTZ-treated ESS mice showed markedly decreased Th17 cells, germinal center B cells and plasma cells in the peripheral lymphoid organs. In addition, adoptively transferred wild type naive CD4(+) T cells rapidly differentiated into Th17 cells and induced salivary dysfunction in IL-17-deficient mice immunized for ESS induction. However, BTZ treatment profoundly suppressed the donor T-cell-derived Th17 response and ameliorated the reduction in salivary secretion in IL-17-deficient recipient mice. Taken together, our findings demonstrate that proteasome inhibition can effectively ameliorate ESS by suppressing the Th17 response, which may contribute to the development of a novel therapeutic strategy for the treatment of SS.