The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of nuclear factor-κB ligand (RANKL) expression in osteogenic cells such as osteoblasts and periodontal ligament cells. However, the detailed mechanism underlying immune–bone cell interactions in periodontitis is not fully understood. Here, we performed single-cell RNA-sequencing analysis on mouse periodontal lesions and showed that neutrophil–osteogenic cell crosstalk is involved in periodontitis-induced bone loss. The periodontal lesions displayed marked infiltration of neutrophils, and in silico analyses suggested that the neutrophils interacted with osteogenic cells through cytokine production. Among the cytokines expressed in the periodontal neutrophils, oncostatin M (OSM) potently induced RANKL expression in the primary osteoblasts, and deletion of the OSM receptor in osteogenic cells significantly ameliorated periodontitis-induced bone loss. Epigenomic data analyses identified the OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this enhancer showed decreased periodontal bone loss while maintaining physiological bone metabolism. These findings shed light on the role of neutrophils in bone regulation during bacterial infection, highlighting the novel mechanism underlying osteoimmune crosstalk.

免疫基质细胞相互作用在健康和疾病中发挥着关键作用。牙周炎是人类最常见的传染病，免疫细胞在口腔粘膜中积聚，并通过诱导成骨细胞和牙周膜细胞等成骨细胞中核因子κB受体激活剂配体（RANKL）的表达来促进骨质破坏。然而，牙周炎中免疫-骨细胞相互作用的详细机制尚不完全清楚。在这里，我们对小鼠牙周病变进行了单细胞 RNA 测序分析，结果表明中性粒细胞与成骨细胞的串扰参与了牙周炎引起的骨质流失。牙周病变显示出明显的中性粒细胞浸润，计算机分析表明中性粒细胞通过细胞因子的产生与成骨细胞相互作用。在牙周中性粒细胞表达的细胞因子中，制瘤素 M (OSM) 有效诱导原代成骨细胞中 RANKL 的表达，而成骨细胞中 OSM 受体的缺失可显着改善牙周炎引起的骨质流失。表观基因组数据分析确定了成骨细胞中 OSM 调节的 RANKL 增强子区域，缺乏该增强子的小鼠表现出牙周骨丢失减少，同时维持生理性骨代谢。这些发现揭示了中性粒细胞在细菌感染期间骨调节中的作用，强调了骨免疫串扰背后的新机制。