Ligature-induced periodontitis promotes Dnmt3aR878H-driven clonal hematopoiesis.

Characterized by somatic mutations (e.g., DNMT3A) in blood cells, clonal hematopoiesis (CH) is an age-related process wherein mutated hematopoietic stem and progenitor cells (HSPC) expand. This expansion thereby increases the risk of allcause mortality, myeloid hematologic malignancies and other non-malignant disorders, yet the risk factors that contribute to CH are still largely unknown. Periodontitis induces low-grade systemic inflammation and affects an estimated 62% of dentate adults globally, which may influence CH-associated pathologies. Periodontitis was modeled by bilateral maxillary second-molar ligation in mice; CH was established using hematopoietic-specific Dnmt3aR878H mutant mice. Periodontal bone destruction was assessed via micro-computed tomography and hematoxilin and eosin staining. Changes in bone marrow HSPC, peripheral blood cells, and gingival immune cells were analyzed by flow cytometry. Key molecular mediators were identified through transcriptomic sequencing of sorted gingival myeloid cells and serum cytokine arrays. Results showed that ligature-induced periodontitis (LIP) promoted Dnmt3aR878H-driven clonal hematopoiesis, manifested as a myeloid-biased phenotype characterized by increased myeloid cells in the gingiva and peripheral blood. The selective enrichment of the Dnmt3aR878H clones during LIP is primarily because Dnmt3aR878H HSC exhibit enhanced resistance and maintain competitive advantages within inflammatory microenvironments. Transcriptomic analysis revealed upregulation of Ccl17 in gingival R878H myeloid cells, which was corroborated by elevated serum and bone marrow levels of CCL17. The CCL17 upregulation drove myeloid cells recruitment to the gingiva, exacerbating periodontitis while simultaneously reinforcing Dnmt3aR878H HSC expansion. This study highlights the necessity of controlling local chronic inflammation, such as periodontitis, in the clinical management of CH.