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.