Inflammatory Osteoclasts Prime TNFα-Producing CD4+ T Cells and Express CX3CR1
Inflammatory Osteoclasts Prime TNFα-Producing CD4+ T Cells and Express CX3CR1
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DOI：
10.1002/jbmr.2868
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发表时间：
2016-10-01
影响因子：
6.2
通讯作者：
Blin-Wakkach, Claudine
中科院分区：
文献类型：
--
作者：
Ibanez, Lidia;Abou-Ezzi, Grazia;Blin-Wakkach, Claudine
骨破坏是慢性风湿性疾病的标志。虽然破骨细胞在骨丢失中的作用已经明确，但尽管它们起源于单核细胞，但它们在炎症反应中的作用尚未研究。此外，缺乏特异性标志物来表征炎症条件下产生的破骨细胞。在此，我们探讨了炎性破骨细胞的表型及其在炎症性肠病相关骨破坏背景下对CD 4（+）T细胞反应的影响。我们使用了通过将初始CD 4（+）T细胞转移到Rag 1（-/-）小鼠中诱导的结肠炎的良好表征模型，其与严重的骨破坏相关。我们建立了一种新的方法来分选体外产生的纯破骨细胞，通过FACS和qPCR分析其表型和特异性免疫反应。我们证明，结肠炎小鼠产生的破骨细胞诱导产生TNF α的CD 4（+）T细胞的出现，而健康小鼠产生的破骨细胞以抗原依赖性方式诱导CD 4（+）FoxP 3（+）调节性T细胞。这种差异与破骨细胞来源于单核细胞或树突状细胞、它们的细胞因子表达模式以及它们的环境有关。我们确定CX（3）CR 1是炎性破骨细胞的标志物，并证明CX（3）CR 1（+）破骨细胞的分化受IL-17体外控制。这项工作是第一次证明，除了参与骨破坏，破骨细胞也诱导免疫原性CD 4（+）T细胞反应后炎症。他们强调CX（3）CR 1是炎症性慢性疾病抗吸收和抗炎治疗的新型双重靶点。(C)2016年美国骨与矿物质研究学会。
Bone destruction is a hallmark of chronic rheumatic diseases. Although the role of osteoclasts in bone loss is clearly established, their implication in the inflammatory response has not been investigated despite their monocytic origin. Moreover, specific markers are lacking to characterize osteoclasts generated in inflammatory conditions. Here, we have explored the phenotype of inflammatory osteoclasts and their effect on CD4(+) T cell responses in the context of bone destruction associated with inflammatory bowel disease. We used the well-characterized model of colitis induced by transfer of naive CD4(+) T cells into Rag1(-/-) mice, which is associated with severe bone destruction. We set up a novel procedure to sort pure osteoclasts generated in vitro to analyze their phenotype and specific immune responses by FACS and qPCR. We demonstrated that osteoclasts generated from colitic mice induced the emergence of TNF alpha-producing CD4(+) T cells, whereas those generated from healthy mice induced CD4(+)FoxP3(+) regulatory T cells, in an antigen-dependent manner. This difference is related to the osteoclast origin from monocytes or dendritic cells, to their cytokine expression pattern, and their environment. We identified CX(3)CR1 as a marker of inflammatory osteoclasts and we demonstrated that the differentiation of CX(3)CR1(+) osteoclasts is controlled by IL-17 in vitro. This work is the first demonstration that, in addition to participating to bone destruction, osteoclasts also induce immunogenic CD4(+) T cell responses upon inflammation. They highlight CX(3)CR1 as a novel dual target for antiresorptive and anti-inflammatory treatment in inflammatory chronic diseases. (C) 2016 American Society for Bone and Mineral Research.