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Brain-derived HMGB1 mediates periodontal inflammation after ischemic stroke through the STAT3/NLRP3 inflammasome

Jin Wang1, Jiehua Zhang2, Yingze Ye1

  • 1Central Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, China; Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.

International Immunopharmacology
|June 4, 2026
PubMed

Insights

Stroke rapidly causes periodontal inflammation via brain-derived high-mobility group box 1 (HMGB1) and hypothalamic-pituitary-adrenal (HPA) axis activation. HMGB1 inhibition reduces inflammation, highlighting its therapeutic potential in brain-oral crosstalk.

Area of Science:

  • Neuroscience
  • Immunology
  • Periodontology

Background:

  • Ischemic stroke is known to cause immunosuppression and worsen peripheral conditions like periodontitis.
  • The direct impact of stroke on periodontal tissues remains unclear.

Purpose of the Study:

  • To investigate the direct impact of ischemic stroke on periodontal tissues.
  • To elucidate the role of high-mobility group box 1 (HMGB1) in post-stroke periodontal inflammation.
  • To explore the involvement of the hypothalamic-pituitary-adrenal (HPA) axis in this process.

Main Methods:

  • Transient middle cerebral artery occlusion (MCAO) mouse model.
  • Assessment of periodontal inflammation markers, including epithelial disruption, alveolar bone loss, osteoclasts, and NLRP3 inflammasome activation.
  • Neuronal and circulating HMGB1 detection, fluorescent tracing of brain-derived HMGB1, and HPA axis activation assessment (CRH, ACTH, corticosterone).
  • In vitro studies using gingival fibroblasts treated with recombinant HMGB1 and STAT3 signaling modulators.
  • Pharmacological intervention using HMGB1 inhibitor Glycyrrhizin (Gly) and STAT3 activator Colivelin.

Main Results:

  • Stroke rapidly induced periodontal inflammation, characterized by epithelial disruption, bone loss, increased osteoclasts, and NLRP3 inflammasome activation.
  • Brain-derived HMGB1 translocated from the nucleus, crossed the disrupted blood-brain barrier, and contributed to periodontal HMGB1 levels.
  • Stroke activated the HPA axis and increased hypothalamic HMGB1.
  • HMGB1 induced inflammation in gingival fibroblasts via STAT3 signaling.
  • Glycyrrhizin treatment attenuated periodontal inflammation by suppressing HMGB1 and HPA axis hyperactivation.

Conclusions:

  • Brain-derived HMGB1 is a key mediator of post-stroke periodontal inflammation through direct migration and HPA axis activation.
  • HMGB1 represents a critical link in brain-oral crosstalk.
  • HMGB1 inhibition presents a potential therapeutic strategy for managing post-stroke periodontal complications.
Keywords:
HMGB1Ischemic strokeNLRP3 inflammasomePeriodontal inflammationSTAT3 signaling pathway

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