Human β-defensin 2 enhances IL-1β production and pyroptosis through P2X7-mediated NLRP3 expression in macrophages

Periodontal disease is the leading cause of tooth loss,which is also a high-risk factor for other diseases including oral cancer and cardiovascular disease.Periodontitis is one of the most common type of periodontal diseases.Interleukin-1β(IL-1β)plays a key role in the pathogenesis of periodontitis.However,the mechanism how IL-1βis produced during periodontitis is still unclear.In the present study,we found that humanβ-defensin 2(hBD2)enhances IL-1βproduction through an LPS-primed human acute monocytic leukemia(THP-1)macrophage model.Inhibition of P2X purinoceptor 7(P2X7)reduced hBD2-enhanced IL-1βproduction.Incubation of LPS-primed THP-1 macrophages with potassium chloride also suppressed hBD2-enhanced IL-1βproduction.Silence of inflammasome adaptor Nod-like receptor family pyrin domain containing 3(NLRP3)led to reduced hBD2-enhanced IL-1βproduction.Likewise,inhibition of caspase-1 also resulted in the decrease of IL-1β.Moreover,an ethidium bromide uptake test indicated that hBD2-activated caspase-1 mediated pyroptotic pore formation.Subsequent lactate dehydrogenase detection and flow cytometric analysis indicated that hBD2 also induced pyroptosis.In brief,these findings illustrated not only the mechanism of hBD2 in enhancing the inflammatory response,but also provided novel therapeutic targets for periodontitis.

Restoring periodontal tissue homoeostasis prevents cognitive decline by reducing the number of Serpina3nhigh astrocytes in the hippocampus

Cognitive decline has been linked to periodontitis through an undetermined pathophysiological mechanism.This study aimed to explore the mechanism underlying periodontitis-related cognitive decline and identify therapeutic strategies for this condition.Using single-nucleus RNA sequencing we found that changes in astrocyte number,gene expression,and cell‒cell communication were associated with cognitive decline in mice with periodontitis.In addition,activation of the NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome was observed to decrease the phagocytic capability of macrophages and reprogram macrophages to a more proinflammatory state in the gingiva,thus aggravating periodontitis.To further investigate this finding,lipid-based nanoparticles carrying NLRP3 siRNA(NPsiNLRP3)were used to inhibit overactivation of the NLRP3 inflammasome in gingival macrophages,restoring the oral microbiome and reducing periodontal inflammation.Furthermore,gingival injection of NPsiNLRP3 reduced the number of Serpina3nhigh astrocytes in the hippocampus and prevented cognitive decline.This study provides a functional basis for the mechanism by which the destruction of periodontal tissues can worsen cognitive decline and identifies nanoparticle-mediated restoration of gingival macrophage function as a novel treatment for periodontitis-related cognitive decline.