Resolvin D1 alleviates periodontitis by promoting FPR2-dependent macrophage pro-resolving polarization and efferocytosis.

INTRODUCTION: Periodontitis is a chronic inflammatory disease driven by dysregulated host responses and failed resolution of inflammation, leading to progressive periodontal tissue destruction. This resolution failure is critically linked to impaired macrophage efferocytosis and a deficiency in endogenous specialized pro-resolving mediators such as Resolvin D1 (RvD1). OBJECTIVES: This study aimed to determine if exogenous RvD1 can restore periodontal homeostasis and to define the formyl peptide receptor 2 (FPR2)-dependent mechanisms governing macrophage reprogramming and the clearance of necroptotic cells. METHODS: We integrated two independent human single-cell RNA sequencing (scRNA-seq) datasets from gingival and periodontal tissues, with a murine ligature-induced periodontitis model using wild-type (Fpr2fl/fl) and myeloid-specific Fpr2 conditional knockout (Fpr2Lyz2-cKO) mice. Therapeutic efficacy was assessed via scRNA-seq, micro-CT, and histology, while downstream molecular pathways were validated through in vivo and ex vivo plus in vitro macrophage functional and signaling assays. RESULTS: Human scRNA-seq analysis revealed a resolution-deficient immune landscape in periodontitis, characterized by impaired macrophage efferocytosis, increased necroptotic signatures, and reduced RvD1 biosynthetic capacity; these abnormalities were largely reversed following periodontal therapy. In vivo, RvD1 significantly reduced alveolar bone loss and decreased necroptotic burden in Fpr2fl/fl mice but not in Fpr2Lyz2-cKO mice. Single-cell profiling demonstrated that RvD1 remodeled the myeloid compartment, promoting monocyte differentiation toward pro-resolving macrophages marked by elevated expression of Chil3, Fn1, and Arg1. Pseudotime trajectory mapping, corroborated by functional engulfment assays, identified an RvD1-induced efferocytosis-competent macrophage state. Mechanistically, RvD1 suppressed the p38 mitogen-activated protein kinase (MAPK)-ADAM17 signaling axis, preventing CD14 cleavage and enhancing recognition and clearance of necroptotic cells. Deletion of Fpr2 in myeloid lineage cells abolished these effects. CONCLUSIONS: This study proposes an RvD1-FPR2-p38 MAPK/ADAM17-CD14 axis that integrates macrophage reprogramming with efficient efferocytotic clearance to resolve periodontal inflammation. Targeting this pathway represents a host-directed immunomodulatory strategy for the treatment of periodontitis and potentially other chronic inflammatory diseases.