Brain-derived HMGB1 mediates post-stroke periodontal inflammation through both direct migration to periodontal tissues and HPA axis activation, operating via the STAT3/NLRP3 inflammasome pathway, highlighting HMGB1 as a critical link in brain-oral crosstalk and a potential therapeutic target.
Key Findings
Results
Ischemic stroke rapidly induced periodontal inflammation in a mouse model, including epithelial disruption, alveolar bone loss, increased osteoclasts, and NLRP3 inflammasome activation.
A transient middle cerebral artery occlusion (MCAO) mouse model was used to induce ischemic stroke.
Periodontal changes observed included epithelial disruption, alveolar bone loss, and increased osteoclast numbers.
NLRP3 inflammasome activation was detected in periodontal tissues following stroke.
These peripheral inflammatory effects occurred despite the primary injury being confined to the brain.
Results
Neuronal HMGB1 translocated from the nucleus and was released into circulation after stroke, coinciding with disruption of the blood-brain barrier and elevated circulating HMGB1 levels.
HMGB1 nuclear-to-cytoplasmic translocation was observed in neurons following MCAO.
Blood-brain barrier disruption was documented concurrently with HMGB1 release.
Elevated circulating HMGB1 levels were detected in peripheral blood following stroke.
This nuclear translocation and release pattern is consistent with HMGB1's role as a damage-associated molecular pattern (DAMP).
Results
Brain-derived HMGB1 directly migrated to periodontal tissues and contributed to the periodontal HMGB1 pool after MCAO.
Fluorescent tracing using intracerebroventricular injection of 5-FAM-labeled HMGB1 was employed to track brain-derived HMGB1.
Longitudinal periodontal fluorescence quantification confirmed accumulation of brain-derived HMGB1 in periodontal tissues.
ELISA of gingival tissue measuring both total HMGB1 and 5-FAM-HMGB1 confirmed the presence of brain-derived HMGB1 in the periodontium.
This direct migration pathway represents a novel mechanism of brain-to-oral tissue communication.
Results
Stroke increased hypothalamic HMGB1 and activated the hypothalamic-pituitary-adrenal (HPA) axis, representing a second pathway by which brain-derived HMGB1 contributed to periodontal inflammation.
Hypothalamic HMGB1 levels were elevated following MCAO.
HPA axis activation was indicated by increased corticotropin-releasing hormone (CRH) in the hypothalamus.
Elevated serum adrenocorticotropic hormone (ACTH) and corticosterone were measured as downstream markers of HPA axis hyperactivation.
HPA axis activation represents a neuroendocrine pathway distinct from direct HMGB1 migration through which stroke affects peripheral tissues.
Results
Recombinant HMGB1 induced inflammatory responses in gingival fibroblasts via STAT3 signaling.
In vitro experiments using gingival fibroblasts were performed with recombinant HMGB1 treatment.
STAT3 (signal transducer and activator of transcription 3) signaling was identified as the downstream pathway activated by HMGB1 in gingival fibroblasts.
This finding establishes a direct mechanistic link between HMGB1 and periodontal cell inflammation.
STAT3 phosphorylation was measured as the indicator of pathway activation.
Results
Treatment with the HMGB1 inhibitor Glycyrrhizin suppressed brain and hypothalamic HMGB1, inhibited HPA axis hyperactivation, reduced STAT3 phosphorylation and NLRP3 signaling, and attenuated periodontal inflammation.
Glycyrrhizin (Gly) was used as a pharmacological HMGB1 inhibitor in the MCAO mouse model.
Glycyrrhizin treatment reduced both brain and hypothalamic HMGB1 levels.
HPA axis hyperactivation markers (CRH, ACTH, corticosterone) were suppressed by Glycyrrhizin treatment.
Reduced STAT3 phosphorylation and NLRP3 inflammasome signaling were observed in periodontal tissues with Glycyrrhizin treatment.
The protective effects of Glycyrrhizin on periodontal inflammation were partially reversed by co-treatment with the STAT3 activator Colivelin, confirming STAT3 as a key mediator in the pathway.
Discussion
Brain-derived HMGB1 mediates post-stroke periodontal inflammation through two parallel mechanisms: direct migration to periodontal tissues and activation of the HPA axis.
The dual-pathway model was supported by fluorescent tracing of brain-derived HMGB1 reaching the periodontium and by HPA axis activation markers.
Both pathways converged on STAT3/NLRP3 inflammasome signaling in periodontal tissues.
Glycyrrhizin inhibition of both pathways simultaneously attenuated periodontal inflammation.
These findings reveal HMGB1 as a critical mechanistic link in brain-oral crosstalk following ischemic stroke.
What This Means
This research suggests that a stroke does not just affect the brain — it can also rapidly trigger inflammation in the gums and surrounding dental structures (periodontium). Using a mouse model of stroke, researchers found that after a brain attack, a protein called HMGB1 — normally kept safely inside brain cell nuclei — leaks out of neurons, crosses into the bloodstream through a damaged blood-brain barrier, and travels to periodontal tissues where it contributes to gum inflammation, bone loss around the teeth, and activation of inflammatory pathways. The researchers used a fluorescent-labeling technique to physically track brain-derived HMGB1 as it moved from the brain to the gums, providing direct evidence of this brain-to-oral tissue communication.
The study also found a second pathway linking stroke to gum disease: HMGB1 accumulated in the hypothalamus (a brain region that controls hormonal stress responses), triggering overactivation of the hypothalamic-pituitary-adrenal (HPA) axis — the body's central stress hormone system. This led to elevated stress hormones (including corticosterone) that likely further promoted periodontal inflammation. In cell culture experiments, HMGB1 was shown to directly activate inflammatory signaling (through a protein called STAT3) in gingival fibroblasts, the connective tissue cells of the gums.
Importantly, treating mice with Glycyrrhizin — a compound derived from licorice root that blocks HMGB1 — reduced brain HMGB1 release, dampened the stress hormone response, and protected periodontal tissues from stroke-induced inflammation. These effects were partially reversed when a STAT3 activator was given simultaneously, confirming that STAT3 is a key step in the inflammatory chain. This research suggests that controlling HMGB1 after a stroke could potentially help protect not only the brain but also peripheral tissues like the periodontium, and points to a biological basis for the clinical observation that stroke patients often experience worsening oral health.
Wang J, Zhang J, Ye Y, Gao Y, Li Y, Zhu H, et al.. (2026). Brain-derived HMGB1 mediates periodontal inflammation after ischemic stroke through the STAT3/NLRP3 inflammasome pathway.. International immunopharmacology. https://doi.org/10.1016/j.intimp.2026.116962