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.

中文翻译：

---

上皮 RANKL 通过 Langerhans 细胞限制实验性牙周炎


由于其驱动破骨细胞分化的能力，核因子 kappa-β 配体的受体激活剂 （RANKL） 被认为对牙周炎产生病理影响。然而，RANKL 最初被确定为树突状细胞 （DC） 的激活剂，由 T 细胞表达，并对免疫系统表现出多种影响。因此，作为骨骼和免疫系统之间的桥梁，RANKL 很可能在牙周炎中起着更复杂的作用。使用结扎诱导的牙周炎 （LIP），检测到快速的牙槽骨丢失，即使结扎仍然存在，该丢失后来也停止了。LIP 的这个晚期也与牙龈中的免疫抑制状况有关。进一步的研究表明，结扎促使表达 RANK 的朗格汉斯细胞 （LCs） 和 EpCAM+ DC（牙龈上皮的抗原呈递细胞 （APC））立即迁移到淋巴结，随后牙龈中 T 调节 （Treg） 细胞扩增。随后，结扎的牙龈被单核细胞衍生的表达 RANK 的 EpCAM+ DC 重新填充，而牙龈上皮细胞上调 RANKL 表达。用单克隆抗体阻断 RANKL 信号传导可显著降低牙龈中 Treg 细胞的频率并阻止牙龈免疫抑制。此外，RANKL 信号转导促进了 LCs 与骨髓前体的区分。为了进一步研究 RANKL 的作用，我们使用了 K14-RANKL 小鼠，其中 RANKL 由牙龈上皮细胞过表达。升高的 RANKL 表达改变了上皮内 LCs 和 EpCAM+ DCs 的稳态频率，有利于 LCs 而不是 EpCAM+ DCs。 结扎放置后，在 K14-RANKL 小鼠牙龈中观察到 Treg 细胞水平升高，牙槽骨丢失显着减少。这些发现表明，牙龈上皮细胞和 APC 之间的 RANKL-RANK 相互作用对于抑制牙龈炎症至关重要，突出了 RANKL 在牙周炎中的保护性免疫作用，而该作用因其破骨细胞生成活性而被忽视。