Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai, China, and Center for Autoimmune Musculoskeletal and Hemaopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, New York.
Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai, China, and The Joint Center for Infection and Immunity, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, China.
Arthritis Rheumatol. 2021 Aug;73(8):1467-1477. doi: 10.1002/art.41677. Epub 2021 Jul 7.
Systemic lupus erythematosus (SLE) involves kidney damage, and the inflammasome-caspase-1 axis has been demonstrated to promote renal pathogenesis. The present study was designed to explore the function of the Absent in Melanoma 2 (Aim2) protein in SLE.
Female wild-type Aim2 , Aim2 Ifnar1 , Aim2 Rag1 , and Asc mice ages 8-10 weeks received 1 intraperitoneal injection of 500 μl pristane or saline, and survival of mice was monitored twice a week for 6 months.
The absence of Aim2, but not Asc, led to enhanced SLE in mice that received pristane treatment. Increased immune cell infiltration and type I interferon (IFN) signatures in the kidneys of Aim2 mice coincided with severity of lupus, which was alleviated by blockade of Ifnar1-mediated signal. Adaptive immune cells were also involved in the glomerular lesions of Aim2 mice after pristane challenge. Importantly, even in the absence of pristane, plasmacytoid dendritic cells in the kidneys of Aim2 mice were significantly increased compared to control animals. Accordingly, transcriptome analysis revealed that Aim2 deficiency led to enhanced expression of type I IFN-induced genes in the kidneys even at an early developmental stage. Mechanistically, Aim2 bound ubiquitin-conjugating enzyme 2i (Ube2i), which mediates sumoylation-based suppression of type I IFN expression deficiency of Aim2 decreased cellular sumoylation, resulting in an augmented type I IFN signature and kidney pathogenesis.
The present study demonstrates a critical role for Aim2 in an optimal Ube2i-mediated sumoylation-based suppression of type I IFN generation and development of SLE. As such, the Aim2-Ube2i axis can thus be a novel target for intervention in SLE.
系统性红斑狼疮（SLE）涉及肾脏损伤，炎症小体-半胱天冬酶-1 轴已被证明可促进肾脏发病机制。本研究旨在探讨 Absent in Melanoma 2（Aim2）蛋白在 SLE 中的功能。
8-10 周龄的雌性野生型 Aim2、Aim2 Ifnar1、Aim2 Rag1 和 Asc 小鼠接受 1 次腹腔内注射 500μl 角鲨烯或生理盐水，每周监测两次，持续 6 个月。
缺乏 Aim2，但不是 Asc，导致接受角鲨烯治疗的小鼠 SLE 加重。Aim2 小鼠肾脏中免疫细胞浸润和 I 型干扰素（IFN）特征增加与狼疮严重程度一致，用 Ifnar1 介导的信号阻断可减轻。适应性免疫细胞也参与了 pristane 挑战后 Aim2 小鼠的肾小球病变。重要的是，即使在没有 pristane 的情况下，Aim2 小鼠肾脏中的浆细胞样树突状细胞也明显高于对照动物。相应地，转录组分析显示，即使在早期发育阶段，Aim2 缺乏也会导致肾脏中 I 型 IFN 诱导基因的表达增强。机制上，Aim2 与泛素连接酶 2i（Ube2i）结合，后者介导基于 SUMOylation 的 I 型 IFN 表达抑制，Aim2 缺乏会降低细胞 SUMOylation，从而导致 I 型 IFN 特征和肾脏发病机制增强。
本研究表明 Aim2 在 Ube2i 介导的基于 SUMOylation 的 I 型 IFN 产生和 SLE 发展的最佳抑制中起关键作用。因此，Aim2-Ube2i 轴可以成为 SLE 干预的新靶点。
