IL-6-PAD4 axis in the earliest phase of arthritis in knock-in gp130F759 mice, a model for rheumatoid arthritis
IL-6-PAD4 axis in the earliest phase of arthritis in knock-in gp130F759 mice, a model for rheumatoid arthritis
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类风湿性关节炎模型 gp130F759 敲入小鼠关节炎早期阶段的 IL-6-PAD4 轴
DOI：
10.1136/rmdopen-2018-000853
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发表时间：
2019
期刊：
影响因子：
6.2
通讯作者：
Ishihara Katsuhiko
中科院分区：
文献类型：
--
作者：
Yahagi Ayano;Saika Taro;Hirano Hiroyasu;Takai-Imamura Miwa;Tsuji Fumio;Aono Hiroyuki;Iseki Masanori;Morita Yoshitaka;Igarashi Hideya;Saeki Yukihiko;Ishihara Katsuhiko
人类疾病的动物模型对于阐明发病前或发病前后的分子机制特别有价值。作为类风湿性关节炎（RA）的模型，我们利用敲入小鼠gp 130 F759。它们在gp 130中具有Y 759 F突变，gp 130是白细胞介素6（IL-6）家族细胞因子的共同受体亚基。儿童关节炎在8个月左右发病，1岁左右发病率达100%。在临床过程中仔细检查发现，在5个月大的关节灵活性非常微妙的阻力。因此，gp 130 F759的病理生理变化进行了检查，解剖分子机制的临床前阶段的RA。MethodsSSeverity的关节炎在gp 130 F759进行了评估与临床评分系统和组织学定量。检测血清细胞因子、自身抗体和C反应蛋白（CRP）水平。滑膜中的变化进行了分析，通过实时PCR，流式细胞仪和免疫组化。ResultsAround 5个月大，各种类型的细胞因子，类风湿因子（RF），抗环瓜氨酸肽IgM和CRP的gp 130 F759血清中增加。观察到新生血管形成、滑膜增生和纤维化增强。IL-6可诱导中性粒细胞表达Padi 4，IL-6可诱导中性粒细胞表达Padi 4。磷酸化STAT 3和PAD 4蛋白在滑膜中检测到增加。gp 130 F759中IL-6的缺失使关节中PAD 4蛋白的量正常化。ConclusionThe IL-6-PAD 4轴在gp 130 F759中关节炎的最早期起作用，这与早期RA有关。
ObjectiveAnimal models for human diseases are especially valuable for clarifying molecular mechanisms before or around the onset. As a model for rheumatoid arthritis (RA), we utilise knock-in mice gp130F759. They have a Y759F mutation in gp130, a common receptor subunit for interleukin 6 (IL-6) family cytokines. Definitive arthritis develops around 8 months old and the incidence reaches 100% around 1 year old. Careful examination in the clinical course revealed very subtle resistance in flexibility of joints at 5 months old. Therefore, pathophysiological changes in gp130F759 were examined to dissect molecular mechanisms for preclinical phase of RA.MethodsSeverity of arthritis in gp130F759 was evaluated with a clinical score system and histological quantification. Serum cytokines, autoantibodies and C reactive protein (CRP) were measured. Changes in the synovium were analysed by real-time PCR, flow cytometry and immunohistochemistry.ResultsAround 5 months old, various types of cytokines, rheumatoid factor (RF), anti-circular citrullinated peptide IgM and CRP increased in the sera of gp130F759. Enhancement of neovascularisation, synovial hyperplasia and fibrosis was observed. Also, increases in haematopoietic cells dominated by innate immune cells and gene expression ofIl6andPadi4were detected in the joints.Il6was expressed by non-haematopoietic synovial cells, whereas PAD4 protein was detected in the synovial neutrophils.Padi4is induced in neutrophils in vitro by IL-6. Increases of phospho-STAT3 and PAD4 protein were detected in the synovium. Deletion of IL-6 in gp130F759 normalised the amount of PAD4 protein in the joints.ConclusionThe IL-6-PAD4 axis operates in the earliest phase of arthritis in gp130F759, implicating it in early RA.