The oral-immune axis: neutrophil extracellular traps mediate the link between periodontitis and autoimmune diseases

Epidemiological and clinical evidence supports a strong association between periodontitis and autoimmune diseases. This review systematically elucidates the pivotal role of the "oral-immune axis" in this relationship, focusing on neutrophil extracellular traps (NETs) as key mediators. Periodontal pathogens can compromise the gingival epithelial barrier, induce excessive NETs formation within the periodontium, facilitate systemic dissemination of pathogens, and promote their ectopic spread to organs such as the joints, pancreas, and kidneys. These processes, in turn, may activate neutrophils to release additional NETs. NETs can aggravate the pathology of various autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus, through mechanisms such as exposure of autoantigens, amplification of inflammatory cascades, and activation of adaptive immune responses. This article further discusses the reverse regulatory role of the oral-immune axis and compares the similarities and differences in NETs in periodontitis and autoimmune diseases. Reinforcing basic periodontal therapy may effectively reduce systemic inflammation and NETs levels, and therapeutic strategies targeting NETs formation, clearance, or function demonstrate potential in interdisciplinary disease management. Altogether, this review provides a novel perspective on the interplay between the oral microbiome and systemic immune diseases, highlighting its substantial translational medical implications.