NR4A1-dependent Ly6Clow monocytes contribute to reducing joint inflammation in arthritic mice through Treg cells
NR4A1-dependent Ly6Clow monocytes contribute to reducing joint inflammation in arthritic mice through Treg cells
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DOI：
10.1002/eji.201646406
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发表时间：
2016-12-01
影响因子：
5.4
通讯作者：
Gosselin, Jean
中科院分区：
文献类型：
--
作者：
Brunet, Alexandre;LeBel, Manon;Gosselin, Jean
单核细胞对关节炎的生理病理至关重要，但它们在疾病进展和解决中的作用仍有待阐明。在缺乏巡逻淋巴细胞抗原6C（Ly6C（低））单核细胞的NR4A1（-/-）小鼠中，我们发现炎症性Ly6C（高）单核细胞有助于血清转移性关节炎（STIA）模型中关节炎的快速发展。我们的实验表明，巡逻单核细胞不会促进小鼠关节炎的发生和进展，因为在NR4A1（-/-）小鼠中症状的严重程度被放大。此外，我们发现用细胞孢素B (Csn-B)（一种nr4a1特异性激动剂）治疗关节炎野生型（WT）小鼠可显著降低疾病的严重程度。氯膦酸钠对单核细胞缺失小鼠的影响不存在，直到Ly6C（低）单核细胞恢复。在接受Csn-B治疗的NR4A1（-/-）关节炎小鼠中过继转移Ly6C（低）单核细胞可减少关节炎症，支持Ly6C（低）亚群对疾病发展的调节作用。我们的研究结果还表明，给关节炎小鼠注射ccn - b可以提高循环CD4(+)CD25(+)FoxP3(+) Treg细胞的水平，这一过程需要Ly6C（低）单核细胞的存在。综上所述，这些数据表明Ly6C（高）单核细胞参与关节炎的发生和发展，Ly6C（低）单核细胞通过动员Treg细胞有助于减少关节炎症。
Monocytes are central to the physiopathology of arthritis, but their roles in progression and resolution of the disease remain to be clarified. Using NR4A1(-/-) mice, which lack patrolling lymphocyte antigen 6C (Ly6C(low)) monocytes, we found that inflammatory Ly6C(high) monocytes contribute to rapid development of arthritis in a serum transfer-induced arthritis (STIA) model. Our experiments suggest that patrolling monocytes do not promote the initiation and progression of arthritis in mice, as severity of symptoms was amplified in NR4A1(-/-) mice. Moreover, we show that treatment of arthritic wild type (WT) mice with cytosporone B (Csn-B), a NR4A1-specific agonist, significantly reduces severity of disease. Effects of Csn-B were absent in monocyte-depleted mice treated with clodronate until Ly6C(low) monocytes were restored. Adoptive transfer of Ly6C(low) monocytes in arthritic NR4A1(-/-) mice treated with Csn-B reduces joint inflammation, supporting the regulatory role of Ly6C(low) subset on disease development. Our results also reveal that administration of Csn-B to arthritic mice enhances levels of circulating CD4(+)CD25(+)FoxP3(+) Treg cells, a process requiring the presence of Ly6C(low) monocytes. Together, these data indicate that Ly6C(high) monocytes are involved in the initiation and progression of arthritis and Ly6C(low) monocytes contribute to reduce joint inflammation through the mobilization of Treg cells.