In this context, the ‘keystone pathogen’ hypothesis of PD pathogenesis
[6] should be reiterated. Keystone pathogens, such as
P. gingivalis, are those that assert undue influence on the local microbiome, causing dysbiosis and resulting in chronic inflammation. In parallel, but not at odds with this hypothesis
[83][69], is the notion that unresolved inflammation, especially neutrophil-mediated, is the principal driving force for pathogenesis (reviewed in
[84][70]). This notion has received considerable attention of late, involving novel therapeutic approaches targeting neutrophil emigration and clearance through manipulation of CXCL8
[85,86,87][71][72][73] or applying pre-resolving mediators. The latter include resolvins, protectins, maresins, and lipoxins. Given the importance of leukocyte trafficking in inflammation, endogenous positive and negative signaling mediators of inflammation have been referred to as local ‘go’ and ‘stop’ signals. Lipoxins (LX) are an important ‘stop’ signal produced in vivo during inflammation
[88][74]. In an experimental PD model in rabbits, application of LXA4 or over-expression of 15-lipoxygenase promoted reduced inflammatory phenotype and were protective against alveolar bone loss
[89][75]. Resolvin E1 (RvE1) has emerged as particularly efficacious. RvE1 is biosynthesized from eicosapentaenoic acid (EPA) and selectively interacts with specific receptors to inhibit leukocyte infiltration, obtund cytokine generation, and promote PMN apoptosis. The latter favors PMN clearance by macrophages and restoration of tissue homeostasis
[90][76]. Nanomolar doses of RvE1 inhibit RANKL-induced osteoclast growth and differentiation, downregulating bone resorption in vitro
[91][77]. A study of human periodontal ligament stem cells showed that in pro-inflammatory milieu, pluripotency, viability, and cell migration were suppressed, whereas maresin-1 (MaR1) and RvE1 restored tissue regenerative capacity
[92][78]. RvE1 application is also effective at promoting bone preservation in the mouse calvaria model
[93][79] and regenerating bone in the ligature-induced periodontitis in rats
[94][80]. Moreover, shifts in the subgingival microbiota, i.e., dysbiosis, induced with ligature were markedly altered by RvE1; namely,
P.gingivalis was reduced. Simply put, RvE1-mediated regulation of inflammation appears to reverse the dysbiosis coincident with prevention and treatment of inflammatory disease
[94][80].