Depletion of regulatory T cells leads to an exacerbation of delayed-type hypersensitivity arthritis in C57BL/6 mice that can be counteracted by IL-17 blockade.
Depletion of regulatory T cells leads to an exacerbation of delayed-type hypersensitivity arthritis in C57BL/6 mice that can be counteracted by IL-17 blockade.
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DOI：
10.1242/dmm.022905
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发表时间：
2016-04
影响因子：
4.3
通讯作者：
Nansen A
中科院分区：
文献类型：
--
作者：
Atkinson SM;Hoffmann U;Hamann A;Bach E;Danneskiold-Samsøe NB;Kristiansen K;Serikawa K;Fox B;Kruse K;Haase C;Skov S;Nansen A
类风湿性关节炎(RA)的啮齿动物模型已被广泛应用于类风湿性关节炎(RA)发病机制的阐明，并在治疗策略的制定中发挥了重要作用。在这里，我们使用了迟发性过敏性关节炎(DTHA)，这是一种C57BL/6小鼠的模型，影响一只爪子，同步发病，100%外显性，低变异。我们通过选择性去除调节性T细胞(Tregs)来研究调节性T细胞(Tregs)在DTHA中的作用，以及IL-17在Treg缺失中的作用。鉴于Tregs在RA中的相关性，以及开发Treg导向疗法的可能性，该方法可能有助于促进对Tregs在炎症性关节炎中的理解。利用Foxp3基因控制下表达白喉毒素受体(DTR)和增强型绿色荧光蛋白(EGFP)的Foxp3-DTR-EGFP小鼠选择性去除Tregs。用抗IL-17单抗阻断IL-17。DTHA大鼠足爪及其引流淋巴结中Tregs的数量和活性增加，Tregs的耗竭导致疾病加重，表现为足肿胀增加，炎症细胞浸润增加，骨改建增加，炎性介质产生增加，抗瓜氨酸蛋白抗体产生增加。抗IL-17单抗治疗表明，无论是否存在Treg，IL-17对疾病的严重程度都是重要的，IL-17阻断能够将小鼠从Treg耗竭引起的疾病加重中解救出来，并导致RANKL、IL-6和中性粒细胞数量的减少。我们发现Treg对于DTHA的炎症控制和骨重建是重要的。据我们所知，这是第一次在C57BL/6背景下使用Foxp3-DTR-EGFP小鼠进行关节炎模型中Treg耗竭的研究，我们在这里证明了该方法在研究Tregs和IL-17在关节炎中的作用的有效性。摘要：这篇文章增加了对迟发型超敏关节炎的疾病驱动因素和调节因素的理解，迟发型超敏关节炎是一种健壮的、可复制的C57BL/6小鼠关节炎模型。
Rodent models of arthritis have been extensively used in the elucidation of rheumatoid arthritis (RA) pathogenesis and are instrumental in the development of therapeutic strategies. Here we utilise delayed-type hypersensitivity arthritis (DTHA), a model in C57BL/6 mice affecting one paw with synchronised onset, 100% penetrance and low variation. We investigate the role of regulatory T cells (Tregs) in DTHA through selective depletion of Tregs and the role of IL-17 in connection with Treg depletion. Given the relevance of Tregs in RA, and the possibility of developing Treg-directed therapies, this approach could be relevant for advancing the understanding of Tregs in inflammatory arthritis. Selective depletion of Tregs was achieved using a Foxp3-DTR-eGFP mouse, which expresses the diphtheria toxin receptor (DTR) and enhanced green fluorescent protein (eGFP) under control of the Foxp3 gene. Anti-IL-17 monoclonal antibody (mAb) was used for IL-17 blockade. Numbers and activation of Tregs increased in the paw and its draining lymph node in DTHA, and depletion of Tregs resulted in exacerbation of disease as shown by increased paw swelling, increased infiltration of inflammatory cells, increased bone remodelling and increased production of inflammatory mediators, as well as increased production of anti-citrullinated protein antibodies. Anti-IL-17 mAb treatment demonstrated that IL-17 is important for disease severity in both the presence and absence of Tregs, and that IL-17 blockade is able to rescue mice from the exacerbated disease caused by Treg depletion and caused a reduction in RANKL, IL-6 and the number of neutrophils. We show that Tregs are important for the containment of inflammation and bone remodelling in DTHA. To our knowledge, this is the first study using the Foxp3-DTR-eGFP mouse on a C57BL/6 background for Treg depletion in an arthritis model, and we here demonstrate the usefulness of the approach to study the role of Tregs and IL-17 in arthritis. Summary: This paper increases the understanding of disease drivers and regulators in delayed-type hypersensitivity arthritis, a robust and reproducible arthritis model in C57BL/6 mice.