IL-17 sustains the plasma cell response via p38-mediated Bcl-xL RNA stability in lupus pathogenesis
IL-17 sustains the plasma cell response via p38-mediated Bcl-xL RNA stability in lupus pathogenesis
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IL-17 通过 p38 介导的 Bcl-xL RNA 稳定性维持狼疮发病机制中的浆细胞反应
DOI：
10.1038/s41423-020-00540-4
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发表时间：
2020-09-11
影响因子：
24.1
通讯作者：
Lu, Liwei
中科院分区：
文献类型：
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作者：
Ma, Kongyang;Du, Wenhan;Lu, Liwei
最近的研究表明，血浆细胞在自身免疫性疾病（例如全身性红斑狼疮）（SLE）中的核心作用。当前，在SLE发病机理期间，自动反应性浆细胞的表型特征和功能调节在很大程度上尚不清楚。在这项研究中，我们首先发现，在SLE患者和狼疮小鼠中，在IL-17A（IL-17）刺激下，在IL-17受体表达浆细胞的主要子集有效产生了抗DSDNA IgG。使用人源化的小鼠模型，与总SLE PBMC的转移相比，狼疮患者的Th17细胞耗电PBMC的转移导致受体小鼠的血浆细胞反应显着降低，并减轻了肾脏损伤。此外，狼疮小鼠中的长期BRDU掺入在表达IL-17受体的浆细胞中检测到高寿命长的BRDU（+）亚群。狼疮小鼠缺乏IL-17或IL-17受体C（IL-17RC）表现出降低的浆细胞反应降低，自身抗体产生降低，肾脏损伤减少，而Th17细胞的收养转移触发了plasma细胞反应和IL-17缺乏型脂肪小鼠的肾上腺细胞反应和肾脏损伤。在重构的嵌合小鼠中，IL-17RC缺乏导致浆细胞的产生严重受损，但对生发中心B细胞没有明显的影响。进一步的机械研究表明，IL-17通过p38-介导的BCl-Xltranscript稳定显着促进了血浆细胞的存活。总之，我们的发现确定了IL-17在增强狼疮发病机理中自身抗体产生的血浆细胞存活方面的新功能，这可能为SLE治疗提供新的治疗策略。
Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). Currently, both the phenotypic features and functional regulation of autoreactive plasma cells during SLE pathogenesis remain largely unclear. In this study, we first found that a major subset of IL-17 receptor-expressing plasma cells potently produced anti-dsDNA IgG upon IL-17A (IL-17) stimulation in SLE patients and lupus mice. Using a humanized lupus mouse model, we showed that the transfer of Th17 cell-depleted PBMCs from lupus patients resulted in a significantly reduced plasma cell response and attenuated renal damage in recipient mice compared to the transfer of total SLE PBMCs. Moreover, long-term BrdU incorporation in lupus mice detected highly enriched long-lived BrdU+subsets among IL-17 receptor-expressing plasma cells. Lupus mice deficient in IL-17 or IL-17 receptor C (IL-17RC) exhibited a diminished plasma cell response and reduced autoantibody production with attenuated renal damage, while the adoptive transfer of Th17 cells triggered the plasma cell response and renal damage in IL-17-deficient lupus mice. In reconstituted chimeric mice, IL-17RC deficiency resulted in severely impaired plasma cell generation but showed no obvious effect on germinal center B cells. Further mechanistic studies revealed that IL-17 significantly promoted plasma cell survival via p38-mediatedBcl-xLtranscript stabilization. Together, our findings identified a novel function of IL-17 in enhancing plasma cell survival for autoantibody production in lupus pathogenesis, which may provide new therapeutic strategies for the treatment of SLE.