Periodontitis-related myocardial fibrosis by expansion of collagen-producing SiglecF+ neutrophils

Abstract Backgrounds and Aims Patients with periodontitis (PD) are prone to developing myocardial infarction (MI), yet the prognosis and mechanisms remain unclear. Given the presumed close association of neutrophils with both conditions, this study aims to elucidate the roles of neutrophils in mediating the interaction between PD and MI. Methods Three prospective cohorts and PD + MI mouse model were investigated to assess the effects of PD on MI prognosis. Single-cell-RNA sequencing and genome-wide association study were employed to identify the neutrophil subtype involved. To characterize the function of SiglecF+ neutrophils, bone marrow transplantation, Edu-pulse chasing, lineage tracing, and collagen contraction assay were utilized. Adoptive neutrophil transfer, conditional Siglecf knockout and lipid nanoparticles facilitating local SiglecF+ neutrophils depletion was harnessed to explore the roles of SiglecF+ neutrophils in MI repair. Results Persisting but not short-term PD upset MI prognosis (cardiac fibrosis and function) in human and mice. Bone marrow neutrophils of PD were intrinsically skewed toward longer-lived SiglecF+ neutrophil differentiation, a subtype that was converted by GMCSF or TGFβ in PPARγ-dependent manner. SiglecF+ neutrophils were expanded in infarcted PD heart where they deposit collagen and activate fibroblasts to instigate excessive fibrosis. SiglecF+ neutrophil depletion was efficacious for mitigating fibrosis. Conclusions This study demonstrated that long-lasting PD-aggravated MI prognosis by expanding scar-associated SiglecF+ neutrophils into the heart and highlighted the clinical relevance of oral health examination for treating MI in a holistic fashion.