IFN-I-mediated neutropoiesis bias drives neutrophil priming and inflammatory comorbidities.

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.