The Prominent Role of Hematopoietic Peptidyl Arginine Deiminase 4 in Arthritis: Collagen- and Granulocyte Colony-Stimulating Factor-Induced Arthritis Model in C57BL/6 Mice.
The Prominent Role of Hematopoietic Peptidyl Arginine Deiminase 4 in Arthritis: Collagen- and Granulocyte Colony-Stimulating Factor-Induced Arthritis Model in C57BL/6 Mice.
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造血肽精氨酸脱亚胺酶4在C57BL/6小鼠关节炎模型中的重要作用
DOI：
10.1002/art.42093
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发表时间：
2022-07
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全基因组关联研究已经将编码肽精氨酸脱亚胺酶4 （PAD4）的PADI4与类风湿关节炎（RA）联系起来。PAD4促进中性粒细胞胞外陷阱（NET）的形成。我们在C57BL/6小鼠关节炎模型中研究了Padi4的来源和NETs。为了使C57BL/6小鼠在胶原诱导关节炎（CIA）模型中有效使用，我们引入了连续4天的粒细胞集落刺激因子（G-CSF）管理，并在第21天进行加强免疫。该模型评估了全局（Padi4−/−）和造血谱系特异性（Padi4Vav1Cre/+） Padi4缺陷小鼠。G-CSF显著增加CIA患者关节炎的发生率和严重程度。g - csf处理的小鼠血浆中瓜氨酸组蛋白H3 （H3Cit）升高，而载体处理的小鼠血浆中没有升高。免疫荧光显微镜显示g - csf处理小鼠滑膜组织中有H3Cit沉积。在g - csf修饰的CIA模型中，与Padi4+/+小鼠相比，Padi4−/−小鼠患关节炎较少，血清白细胞介素6和血浆H3Cit较低，滑膜组织中瓜氨酸化组蛋白H4较少，显微计算机断层扫描观察到骨侵蚀较少。同样，与Padi4fl/fl小鼠相比，Padi4Vav1Cre/+小鼠患关节炎的几率更小，并且表现出与Padi4−/−小鼠相同的表型。我们成功地开发了一种适用于C57BL/6小鼠的关节炎模型，该模型完全符合高动物福利标准。我们观察到在雄性小鼠中超过90%的关节炎发病率和可检测的NET标记物。该模型与人类类风湿关节炎具有一定的一致性，表明造血PAD4是关节炎发展的重要因素，可能在未来的类风湿关节炎研究中有用。
Genome-wide association studies have connected PADI4, encoding peptidylarginine deiminase 4 (PAD4), with rheumatoid arthritis (RA). PAD4 promotes neutrophil extracellular trap (NET) formation. We studied Padi4 origin and NETs in an arthritis model in C57BL/6 mice. To permit the effective use of C57BL/6 mice in the collagen-induced arthritis (CIA) model, we introduced the administration of granulocyte colony-stimulating factor (G-CSF) for four consecutive days in conjunction with the booster immunization on day 21. The model evaluated global (Padi4−/−) and hematopoietic lineage-specific (Padi4Vav1Cre/+) Padi4-deficient mice. G-CSF significantly increased the incidence and severity of arthritis in CIA. G-CSF-treated mice showed elevated citrullinated histone H3 (H3Cit) in plasma while vehicle-treated mice did not. Immunofluorescent microscopy revealed deposition of H3Cit in synovial tissue in G-CSF-treated mice. Padi4−/− mice developed less arthritis, demonstrating lower serum interleukin 6 and plasma H3Cit, less citrullinated histone H4 in synovial tissue, and less bone erosion observed by micro-computed tomography than Padi4+/+ mice in the G-CSF-modified CIA model. Similarly, Padi4Vav1Cre/+ mice developed less arthritis compared with Padi4fl/fl mice, and presented the same phenotype as Padi4−/− mice. We succeeded in developing an arthritis model suitable for use in C57BL/6 mice that was fully compliant with high animal welfare standards. We observed an over 90% incidence of arthritis in male mice and detectable NET markers. This model, with some futures consistent with human RA, demonstrates that hematopoietic PAD4 is an important contributor to arthritis development and may prove useful in future RA research.
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影响因子：
3.7
作者：
Hemmers S;Teijaro JR;Arandjelovic S;Mowen KA
通讯作者：
Mowen KA
DOI：
10.1084/jem.20100239
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
通讯作者：
Wang Y
影响因子：
4.9
作者：
Rohrbach AS;Hemmers S;Arandjelovic S;Corr M;Mowen KA
通讯作者：
Mowen KA
影响因子：
27.4
作者：
Backlund, Johan;Li, Cuiqin;Holmdahl, Rikard
通讯作者：
Holmdahl, Rikard
DOI：
10.1083/jcb.200806072
发表时间：
2009-01-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Wang Y;Li M;Stadler S;Correll S;Li P;Wang D;Hayama R;Leonelli L;Han H;Grigoryev SA;Allis CD;Coonrod SA
通讯作者：
Coonrod SA