USP22 knockdown attenuates P. gingivalis-induced EndoMT and CNS inflammation: a link between periodontitis and neuroinflammation

Objective Chronic periodontitis is a significant risk factor for systemic disorders. However, the precise mechanism through which the “oral-brain axis” mediates its impact on the central nervous system remains unclear. This study aimed to investigate whether the periodontal pathogen Porphyromonas gingivalis ( P. gingivalis ) induces endothelial-mesenchymal transition (EndoMT), thereby disrupting the blood–brain barrier (BBB) and triggering neuroinflammation, and to elucidate the regulatory role of the deubiquitinating enzyme USP22 in this process. Methods A chronic oral infection model of P. gingivalis was established in mice, which was confirmed by assessing inflammatory factor levels in periodontal tissues. Endothelial tight junction proteins (ZO-1 and Claudin-5), a mesenchymal marker ( α -SMA), and inflammatory mediators (iNOS) were detected by Western blotting. IL-1β and IL-6 mRNA levels were detected by quantitative real-time PCR. Human brain microvascular endothelial cells (HBMECs) were stimulated with P. gingivalis -derived lipopolysaccharide (LPS) to mimic inflammation in vitro . Endothelial-specific knockdown of USP22 in the hippocampus was achieved via adeno-associated virus (AAV) delivery to validate its role in vivo . STRING bioinformatics tool to investigate its potential downstream pathways. Results Oral infection with P. gingivalis successfully induced periodontitis in mice and led to EndoMT in the hippocampus, characterized by downregulation of ZO-1 and Claudin-5 and upregulation of α -SMA, along with inflammatory activation evidenced by elevated levels of iNOS, IL-1β mRNA, and IL-6 mRNA. USP22 expression was significantly upregulated both in hippocampal tissues of P. gingivalis -infected mice and in LPS-exposed HBMECs. Knockdown of USP22 attenuated LPS-induced EndoMT and suppressed the expression of inflammatory markers in HBMECs. Similarly, endothelial-specific knockdown of USP22 mitigated P. gingivalis -induced EndoMT and hippocampal inflammation in vivo . Conclusion These findings demonstrate that P. gingivalis promotes EndoMT and neuroinflammation in the hippocampus. Endothelial-specific inhibition of USP22 alleviates BBB dysfunction and central inflammatory responses, highlighting USP22 as a potential therapeutic target for neuroinflammatory disorders associated with chronic periodontitis.