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Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes
Arthritis Research & Therapy ( IF 4.4 ) Pub Date : 2021-11-16 , DOI: 10.1186/s13075-021-02668-8
Tong Yang 1, 2 , Kai Sun 1, 2 , Chun Wang 2 , Gaurav Swarnkar 3 , Songtao Quan 4 , Dustin Kress 2 , Jianqiu Xiao 2 , Yael Alippe 2 , Hongjun Zheng 3 , Robert H Brophy 3 , Dingjun Hao 1 , Audrey McAlinden 3, 5 , Yousef Abu-Amer 3, 5 , Jie Shen 3 , Gabriel Mbalaviele 2
Affiliation  

Gasdermin D (GSDMD) is cleaved by several proteases including by caspase-1, a component of intracellular protein complexes called inflammasomes. Caspase-1 also converts pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into bioactive IL-1β and IL-18, respectively. GSDMD amino-terminal fragments form plasma membrane pores, which mediate the secretion of IL-1β and IL-18 and cause the inflammatory form of cell death pyroptosis. Here, we tested the hypothesis that GSDMD contributes to joint degeneration in the K/BxN serum transfer-induced arthritis (STIA) model in which autoantibodies against glucose-6-phosphate isomerase promote the formation of pathogenic immune complexes on the surface of myeloid cells, which highly express the inflammasomes. The unexpected outcomes with the STIA model prompted us to determine the role of GSDMD in the post-traumatic osteoarthritis (PTOA) model caused by meniscus ligamentous injury (MLI) based on the hypothesis that this pore-forming protein is activated by signals released from damaged joint tissues. Gsdmd +/+ and Gsdmd−/− mice were injected with K/BxN mouse serum or subjected to MLI to cause STIA or PTOA, respectively. Paw and ankle swelling and DXA scanning were used to assess the outcomes in the STIA model whereas histopathology and micro-computed tomography (μCT) were utilized to monitor joints in the PTOA model. Murine and human joint tissues were also examined for GSDMD, IL-1β, and IL-18 expression by qPCR, immunohistochemistry, or immunoblotting. GSDMD levels were higher in serum-inoculated paws compared to PBS-injected paws. Unexpectedly, ablation of GSDMD failed to reduce joint swelling and osteolysis, suggesting that GSDMD was dispensable for the pathogenesis of STIA. GSDMD levels were also higher in MLI compared to sham-operated joints. Importantly, ablation of GSDMD attenuated MLI-associated cartilage degradation (p = 0.0097), synovitis (p = 0.014), subchondral bone sclerosis (p = 0.0006), and subchondral bone plate thickness (p = 0.0174) based on histopathological and μCT analyses. GSDMD plays a key role in the pathogenesis of PTOA, but not STIA, suggesting that its actions in experimental arthropathy are tissue context-specific.

中文翻译:


Gasdermin D 缺乏可减轻创伤引起的关节炎,但不会减轻自身抗体组装的免疫复合物



Gasdermin D (GSDMD) 可被多种蛋白酶切割,包括 caspase-1,一种称为炎症小体的细胞内蛋白质复合物的组成部分。 Caspase-1 还可将白细胞介素原 1β (pro-IL-1β) 和 IL-18 原分别转化为具有生物活性的 IL-1β 和 IL-18。 GSDMD 氨基末端片段形成质膜孔,介导 IL-1β 和 IL-18 的分泌,并导致细胞死亡的炎症形式焦亡。在这里,我们测试了 GSDMD 导致 K/BxN 血清转移诱导关节炎 (STIA) 模型中关节变性的假设,在该模型中,针对葡萄糖-6-磷酸异构酶的自身抗体促进了骨髓细胞表面致病性免疫复合物的形成,高度表达炎症小体。 STIA 模型的意外结果促使我们确定 GSDMD 在半月板韧带损伤 (MLI) 引起的创伤后骨关节炎 (PTOA) 模型中的作用,该模型基于以下假设:这种成孔蛋白是由受损的韧带释放的信号激活的关节组织。 Gsdmd +/+ 和 Gsdmd−/− 小鼠被注射 K/BxN 小鼠血清或接受 MLI 分别引起 STIA 或 PTOA。爪子和踝关节肿胀以及 DXA 扫描用于评估 STIA 模型中的结果,而组织病理学和微型计算机断层扫描 (μCT) 用于监测 PTOA 模型中的关节。还通过 qPCR、免疫组织化学或免疫印迹检查了小鼠和人类关节组织的 GSDMD、IL-1β 和 IL-18 表达。与注射 PBS 的爪子相比,接种血清的爪子中的 GSDMD 水平较高。出乎意料的是,GSDMD 消融未能减少关节肿胀和骨质溶解,这表明 GSDMD 对于 STIA 的发病机制不是可有可无的。 与假手术关节相比,MLI 中的 GSDMD 水平也较高。重要的是,根据组织病理学和 μCT 分析,GSDMD 消融减轻了 MLI 相关的软骨退化(p = 0.0097)、滑膜炎(p = 0.014)、软骨下骨硬化(p = 0.0006)和软骨下骨板厚度(p = 0.0174)。 GSDMD 在 PTOA 的发病机制中发挥关键作用,但在 STIA 中则不然,这表明其在实验性关节病中的作用具有组织背景特异性。
更新日期:2021-11-16
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