Periodontitis is considered a promoter of many systemic diseases, but the signaling pathways
of this interconnection remain elusive. Recently, it became evident that certain microbial challenges
promote a heightened response of myeloid cell populations to subsequent infections either with the
same or other pathogens. This phenomenon involves changes in the cell epigenetic and transcription,
and is referred to as “trained immunity”. It acts via modulation of hematopoietic stem and progenitor cells (HSPCs). A main modulation driver is the sustained, persistent low-level transmission of
lipopolysaccharide from the periodontal pocket into the peripheral blood. Subsequently, the neutrophil
phenotype changes and neutrophils become hyper-responsive and prone to boosted formation of
neutrophil extracellular traps (NET). Cytotoxic neutrophil proteases and histones are responsible
for ulcer formations on the pocket epithelium, which foster bacteremia and endoxemia. The latter
promote systemic low-grade inflammation (SLGI), a precondition for many systemic diseases and
some of them, e.g., atherosclerosis, diabetes etc., can be triggered by SLGI alone. Either reverting the
polarized neutrophils back to the homeostatic state or attenuation of neutrophil hyper-responsiveness
in periodontitis might be an approach to diminish or even to prevent systemic diseases
