上皮 RANKL 通过朗格汉斯细胞限制实验性牙周炎的发生

Y Netanely, O Barel, R Naamneh, Y Jaber, S Yacoub, Y Saba, K Zubeidat, O Saar, L Eli-Berchoer, S Yona, A Brand, T Capucha, A Wilensky, K Loser, B E Clausen, A-H Hovav
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This late phase of LIP was also linked with immunosuppressive conditions in the gingiva. Further investigation revealed that the ligature prompted an immediate migration of RANK-expressing Langerhans cells (LCs) and EpCAM<sup>+</sup> DCs, the antigen-presenting cells (APCs) of the gingival epithelium, to the lymph nodes, followed by an expansion of T regulatory (Treg) cells in the gingiva. Subsequently, the ligatured gingiva was repopulated by monocyte-derived RANK-expressing EpCAM<sup>+</sup> DCs, while gingival epithelial cells upregulated RANKL expression. Blocking RANKL signaling with monoclonal antibodies significantly reduced the frequencies of Treg cells in the gingiva and prevented gingival immunosuppression. In addition, RANKL signaling facilitated the differentiation of LCs from bone marrow precursors. To further investigate the role of RANKL, we used K14-RANKL mice, in which RANKL is overexpressed by gingival epithelial cells. 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引用次数: 0

摘要

核因子 kappa-β 配体受体激活剂(RANKL)具有驱动破骨细胞分化的能力,因此被认为对牙周炎具有病理影响。然而,RANKL 最初被认为是树突状细胞(DC)的激活剂,由 T 细胞表达,对免疫系统有多种影响。因此,作为骨与免疫系统之间的桥梁,RANKL很可能在牙周炎中扮演着更为复杂的角色。利用结扎诱导的牙周炎(LIP),可以检测到牙槽骨的快速流失,即使结扎仍然存在,这种流失随后也会停止。LIP 的后期阶段还与牙龈的免疫抑制条件有关。进一步的研究发现,结扎会促使牙龈上皮的抗原呈递细胞(APCs)--表达 RANK 的朗格汉斯细胞(LCs)和 EpCAM+ DCs 立即迁移到淋巴结,随后牙龈中的 T 调节(Treg)细胞也会扩张。随后,单核细胞衍生的表达 RANK 的 EpCAM+ DCs 重新填充了结扎的牙龈,而牙龈上皮细胞则上调了 RANKL 的表达。用单克隆抗体阻断RANKL信号传导可显著降低牙龈中Treg细胞的频率,防止牙龈免疫抑制。此外,RANKL 信号还能促进骨髓前体 LCs 的分化。为了进一步研究 RANKL 的作用,我们使用了 K14-RANKL 小鼠,在这种小鼠中,牙龈上皮细胞过量表达 RANKL。RANKL 表达的升高改变了上皮细胞内 LCs 和 EpCAM+ DCs 的稳态频率,LCs 比 EpCAM+ DCs 更受青睐。结扎后,在 K14-RANKL 小鼠的牙龈中观察到了更高水平的 Treg 细胞,牙槽骨流失也显著减少。这些研究结果表明,牙龈上皮细胞和APCs之间的RANKL-RANK相互作用对抑制牙龈炎症至关重要,凸显了RANKL在牙周炎中的保护性免疫作用,而这一作用因其破骨细胞活性而被忽视。
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Epithelial RANKL Limits Experimental Periodontitis via Langerhans Cells.

Due to its capacity to drive osteoclast differentiation, the receptor activator of nuclear factor kappa-β ligand (RANKL) is believed to exert a pathological influence in periodontitis. However, RANKL was initially identified as an activator of dendritic cells (DCs), expressed by T cells, and exhibits diverse effects on the immune system. Hence, it is probable that RANKL, acting as a bridge between the bone and immune systems, plays a more intricate role in periodontitis. Using ligature-induced periodontitis (LIP), rapid alveolar bone loss was detected that was later halted even though the ligature was still present. This late phase of LIP was also linked with immunosuppressive conditions in the gingiva. Further investigation revealed that the ligature prompted an immediate migration of RANK-expressing Langerhans cells (LCs) and EpCAM+ DCs, the antigen-presenting cells (APCs) of the gingival epithelium, to the lymph nodes, followed by an expansion of T regulatory (Treg) cells in the gingiva. Subsequently, the ligatured gingiva was repopulated by monocyte-derived RANK-expressing EpCAM+ DCs, while gingival epithelial cells upregulated RANKL expression. Blocking RANKL signaling with monoclonal antibodies significantly reduced the frequencies of Treg cells in the gingiva and prevented gingival immunosuppression. In addition, RANKL signaling facilitated the differentiation of LCs from bone marrow precursors. To further investigate the role of RANKL, we used K14-RANKL mice, in which RANKL is overexpressed by gingival epithelial cells. The elevated RANKL expression shifted the steady-state frequencies of LCs and EpCAM+ DCs within the epithelium, favoring LCs over EpCAM+ DCs. Following ligature placement, heightened levels of Treg cells were observed in the gingiva of K14-RANKL mice, and alveolar bone loss was significantly reduced. These findings suggest that RANKL-RANK interactions between gingival epithelial cells and APCs are crucial for suppressing gingival inflammation, highlighting a protective immunological role for RANKL in periodontitis that was overlooked due to its osteoclastogenic activity.

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