Dynamin-Related Protein 1 Orchestrates Inflammatory Responses in Periodontal Macrophages via Interaction With Hexokinase 1.

Aim: To explore the potential roles of mitochondrial dysfunction in the initiation of inflammation in periodontal macrophages and to determine the mechanism underlying the involvement of dynamin-related protein 1 (Drp1) in macrophage inflammatory responses through its interaction with hexokinase 1 (HK1).

Materials And Methods: Gingival tissues were collected from patients diagnosed with periodontitis or from healthy volunteers. Drp1 tetramer formation and phosphorylation were analysed using western blot. THP-1 macrophages and RAW264.7 cells were stimulated with Porphyromonas gingivalis (Pg) or Pg lipopolysaccharide (Pg LPS), respectively. Alterations in proteins associated with mitochondrial dynamics were scrutinized via western blot. Immunofluorescence was used to evaluate mitochondrial damage and mitochondrial permeability transition pore (mPTP) opening. Western blot was used to examine the inflammatory markers NLRP3, caspase-1, IL-1β and GSDMD. Protein interactions involving Drp1 were verified through immunoprecipitation.

Results: In periodontitis patient samples, Pg LPS-treated RAW264.7 cells, and Pg-stimulated THP-1 macrophages, over-activated Drp1 was able to drive NLRP3 inflammasome activation and the subsequent release of inflammatory factors. A direct interaction between Drp1 and HK1 was observed, facilitating excessive mPTP opening and subsequent mitochondrial dysfunction.

Conclusion: In the inflammatory milieu of periodontal tissues, Drp1 hyperactivation in the macrophages is implicated in inflammation induction. Modulation of the inflammatory response in periodontal macrophages by Drp1 appears to facilitate mPTP opening.