Rationale: Local chronic inflammation is increasingly recognized as a driver of systemic inflammatory comorbidities; however, the underlying mechanisms remain incompletely understood. This study investigates the impact of periodontitis on the reprogramming of bone marrow hematopoiesis, with a focus on neutropoiesis bias and its contribution to the exacerbation of arthritis. Methods: Single-cell multiomics sequencing was performed on hematopoietic stem and progenitor cells (HSPCs) isolated from control and ligature-induced periodontitis (LIP) mice to characterize transcriptional and epigenetic alterations. Differentiation trajectories and key transcription factors (TFs) governing neutrophil lineage commitment were identified. Neutrophil priming was assessed using Smart-seq2, bulk RNA-seq, and lipopolysaccharide stimulation assays. The functional role of primed neutrophils in arthritis was evaluated through adoptive transfer, in vivo tracking, and functional blockade within a collagen antibody-induced arthritis model. Type I interferon (IFN-I) signaling was interrogated using Ifnar1⁻/⁻ mice and neutralizing antibodies to elucidate mechanistic pathways. Reversibility of neutropoiesis bias and arthritis aggravation was examined following ligature removal to model periodontitis resolution. Results: Transcriptional and chromatin accessibility profiling demonstrated that LIP induces a selective skewing of HSPC differentiation toward the neutrophil lineage. This reprogramming results in sustained expansion of primed neutrophils, which contribute to the aggravation of distal arthritis. Mechanistically, elevated IFN-I levels promote continuous neutropoiesis bias through activation of IFN-I signaling in HSPCs. Rarg and Nr2f6 were identified as potential TFs contributing to IFN-I-mediated neutrophil lineage commitment. Notably, resolution of periodontitis reversed the hematopoietic bias and mitigated arthritis progression. Conclusions: Periodontitis exacerbates arthritis through IFN-I-mediated neutropoiesis bias, emphasizing the necessity of controlling local chronic inflammation in the management of systemic inflammatory comorbidities.

Keywords: hematopoietic stem and progenitor cells; inflammatory comorbidities; neutropoiesis; periodontitis; single-cell multiomics sequencing.

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理由：局部慢性炎症越来越多地被认为是一种系统性炎性疾病共病的驱动因素；然而，其背后的机制尚不完全清楚。本研究调查了牙周炎对骨髓造血重编程的影响，重点关注中性粒细胞偏倚及其在加重关节炎中的作用。方法：通过单细胞多组学测序技术分析对照组和经结扎诱导的牙周炎（LIP）小鼠分离出的造血干细胞和祖细胞 (HSPCs)，以表征转录和表观遗传改变。确定分化轨迹以及控制中性粒细胞谱系承诺的关键转录因子 (TFs)。使用 Smart-seq2、批量 RNA 测序和脂多糖刺激实验评估中性粒细胞激活状态。通过适应性转移、体内追踪以及在胶原抗体诱导的关节炎模型中的功能阻断，评价活化中性粒细胞的功能作用。IFN-I 信号通路使用 Ifnar1⁻/⁻ 小鼠和中和抗体进行探究以阐明机制途径。去除结扎物后对中性粒细胞偏倚及关节炎加重的可逆性进行了检查，用以模拟牙周病缓解情况。结果：转录组学和染色质可访问性分析表明 LIP 导致 HSPC 分化向中性粒细胞谱系倾斜。这种重编程导致活化中性粒细胞持续扩增，并对远端关节炎加重有所贡献。机制上，升高的 IFN-I 水平通过激活 HSPCs 中的 IFN-I 信号传导促进了连续的中性粒细胞偏倚。Rarg 和 Nr2f6 被确定为参与 IFN-I 介导的中性粒细胞谱系承诺的关键转录因子。值得注意的是，牙周病的缓解逆转了造血偏倚并减轻了关节炎进展。结论：牙周病通过 IFN-I 介导的中性粒细胞偏倚加重关节炎，强调在管理系统性炎症共病时控制局部慢性炎症的重要性。

关键词：造血干细胞和祖细胞；炎性共病；中性粒细胞生成；牙周炎；单细胞多组学测序

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