Th22 Cells Promote Osteoclast Differentiation via Production of IL-22 in Rheumatoid Arthritis
Th22 Cells Promote Osteoclast Differentiation via Production of IL-22 in Rheumatoid Arthritis
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DOI：
10.3389/fimmu.2018.02901
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发表时间：
2018-12-10
影响因子：
7.3
通讯作者：
Tanaka, Yoshiya
中科院分区：
文献类型：
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作者：
Miyazaki, Yusuke;Nakayamada, Shingo;Tanaka, Yoshiya
辅助性T细胞（Th）可以分化成功能不同的亚群，并在炎症和自身免疫性疾病如类风湿关节炎（RA）中发挥关键作用。Th22细胞是一种新的分泌白细胞介素-22的细胞亚群。虽然有报道称RA患者滑液中IL-22水平升高，但其病理作用尚不清楚。在这里，我们证明了IL-22是由CD3(+)CD4(+) cc趋化因子受体（CCR）4(+)CCR6(+)CCR10（+）细胞特征性地产生的，它们产生IL-22的能力明显超过其他Th亚群和亚群，因此称为Th22细胞。肿瘤坏死因子- α、IL-6和IL-1 β刺激能有效诱导Th22细胞。活动性RA患者滑膜组织中Th22细胞明显浸润，而骨关节炎（OA）患者则没有。CCL17、CCL20和CCL28分别是CCR4、CCR6和CCR10的趋化因子配体，与OA相比，它们在RA滑膜组织中大量表达。通过体外跨孔迁移实验，Th22细胞向CCL28有效迁移。外周血Th22细胞与单核细胞在巨噬细胞集落刺激因子和核因子受体激活因子- κ B配体存在下共培养诱导破骨细胞形成的效率高于Th1细胞或Th17细胞。此外，IL-22通过促进CD14（+）单核细胞中活化的核因子T细胞c1的表达，显著增强破骨细胞的分化。相反，在培养物中加入ifn - γ可显著减少破骨细胞数量，而IL-17则具有边际效应。IL-22中和抗体抑制Th22细胞与CD14（+）单核细胞共培养的破骨细胞形成。综上所述，共表达趋化因子受体CCR4、CCR6和CCR10的Th22细胞具有很强的组织迁移能力，可在炎症滑膜组织中积累，其中CCL28等配体高表达。因此，Th22细胞具有通过产生IL-22促进破骨细胞分化的能力，因此在RA患者的骨破坏中起关键作用。
T helper (Th) cells can differentiate into functionally distinct subsets and play a pivotal role in inflammatory and autoimmune diseases such as rheumatoid arthritis (RA). Th22 cells have been identified as a new subset secreting interleukin (IL)-22. Although elevated levels of IL-22 in the synovial fluids of RA patients were reported, its pathological roles remain unclear. Here, we demonstrated that IL-22 was characteristically produced from CD3(+)CD4(+)CC-chemokine receptor (CCR)4(+)CCR6(+)CCR10(+) cells and their ability of the production of IL-22 markedly exceeded that of other Th subsets and the subset, thereby, designated Th22 cells. Th22 cells were efficiently induced by the stimulation with tumor necrosis factor-alpha, IL-6, and IL-1 beta. Th22 cells were markedly infiltrated in synovial tissue in patients with active RA, but not in patients with osteoarthritis (OA). CCL17, CCL20, and CCL28, which are chemokine ligands of CCR4, CCR6, and CCR10, respectively, were abundantly expressed in RA synovial tissue compared to OA. By in vitro Trans-well migration assay, Th22 cells efficiently migrated toward CCL28. Co-culture of Th22 cells, which were sorted from peripheral blood, with monocytes in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor (NF)-kappa B ligand induced osteoclasts formation more efficiently than that of either Th1 cells or Th17 cells. Furthermore, IL-22 markedly augmented osteoclast differentiation by promoting nuclear factor of activated T cells c1 expression in CD14(+) monocytes. Contrarily, the addition of IFN-gamma to the culture significantly decreased osteoclasts number, whereas IL-17 had marginal effects. IL-22 neutralizing antibody inhibited osteoclast formation in the co-culture of Th22 cells with CD14(+) monocytes. Collectively, the results indicated that Th22 cells, which co-express chemokine receptors CCR4, CCR6, and CCR10, possess strong potency of tissue migration and accumulate into inflamed synovial tissues where the ligands such as CCL28 are highly expressed. Thus, Th22 cells have the capacity to promote osteoclast differentiation through production of IL-22 and thus play a pivotal role in bone destruction in patients with RA.