Abstract：
Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.
摘要：
牙周炎,一种常见的慢性炎症性疾病,集中体现了宿主免疫系统的显着损害和骨代谢的失衡。巨噬细胞极化，由微环境决定的动态过程，复杂地促进了免疫系统和骨骼重建之间的相互作用，即骨免疫系统。叉头盒蛋白O1（FoxO1）已被证明在介导氧化应激中起着戏剧性的作用，骨量,以及细胞代谢。然而，FoxO1在牙周炎中调节巨噬细胞极化介导的成骨的功能和潜在机制仍有待进一步阐明。这里,我们发现FoxO1的表达与牙周炎密切相关，伴有炎症加重。值得注意的是,在炎症条件下，FoxO1敲低使巨噬细胞极化从M1偏向抗炎M2表型，挽救了受损的成骨潜力。机械上,我们揭示了FoxO1敲低巨噬细胞中过氧化物酶体增殖物激活受体（PPAR）信号转录的增强。同意这一论点，GW9662，PPAR-γ信号的特异性抑制剂，在炎症条件下，巨噬细胞从M2向M1表型的极化大大加剧，成骨潜能减弱。此外,PPAR-γ信号传导激动剂罗格列酮（RSG）用于解决结扎诱导的牙周炎，并减轻炎症。我们的数据为FoxO1在介导巨噬细胞极化调节的骨生成中的功能提供了概念上的证据，该功能可作为牙周炎的新治疗靶标。
