Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss
Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss
复制标题
DOI：
10.4049/jimmunol.1500437
复制
发表时间：
2015-11-01
影响因子：
4.4
通讯作者：
Aoudjit, Fawzi
中科院分区：
文献类型：
--
作者：
El Azreq, Mohammed-Amine;Arseneault, Claudie;Aoudjit, Fawzi
Th 17细胞是炎症和组织损伤（如骨侵蚀）中的关键效应子，但在此过程中调节其活化的机制尚未完全了解。在这项研究中，我们认为细胞因子受体和整合素通路之间的合作，在Th 17-破骨细胞的功能。我们发现人Th 17细胞共表达IL-7 R和胶原结合整合素α 2 β 1（CD 49 b），IL-7通过α 2 β 1整合素增加其与胶原的粘附。此外，人Th 17细胞中两种受体的共同参与协同增强了它们的IL-17产生和它们的破骨细胞生成功能。IL-7 R和α 2 β 1整联蛋白之间的功能合作涉及JAK/PI 3 K/AKT（蛋白激酶B）和MAPK/ERK途径的激活。我们还表明，IL-7诱导的骨丢失在体内与Th 17细胞扩增。此外，用中和mAb阻断α 2 β 1整联蛋白通过减少骨髓中的Th 17细胞数量和减少IL-17和NF-κ B配体的受体激活剂的产生来抑制IL-7诱导的骨丢失和破骨细胞数量。因此，IL-7 R和α 2 β 1整联蛋白之间的合作可以代表与炎性疾病相关的Th 17-破骨细胞功能中的重要致病途径。
Th17 cells are critical effectors in inflammation and tissue damage such as bone erosion, but the mechanisms regulating their activation in this process are not fully understood. In this study, we considered the cooperation between cytokine receptors and integrin pathways in Th17-osteoclast function. We found that human Th17 cells coexpress IL-7R and the collagen-binding integrin alpha 2 beta 1 (CD49b), and IL-7 increases their adhesion to collagen via alpha 2 beta 1 integrin. In addition, coengagement of the two receptors in human Th17 cells cooperatively enhanced their IL-17 production and their osteoclastogenic function. The functional cooperation between IL-7R and alpha 2 beta 1 integrin involves activation of the JAK/PI3K/AKT (protein kinase B) and MAPK/ERK pathways. We also showed that IL-7-induced bone loss in vivo is associated with Th17 cell expansion. Moreover, blockade of alpha 2 beta 1 integrin with a neutralizing mAb inhibited IL-7-induced bone loss and osteoclast numbers by reducing Th17 cell numbers in the bone marrow and reducing the production of IL-17 and the receptor activator of NF-kappa B ligand. Thus, the cooperation between IL-7R and alpha 2 beta 1 integrin can represent an important pathogenic pathway in Th17-osteoclast function associated with inflammatory diseases.