New developments in neutrophil biology and periodontitis.

Neutrophils have been historically associated with antimicrobial functions in acute infections but are now appreciated as functionally versatile cells with critical roles in chronic inflammation. Recent advances in neutrophil biology have contributed to a better understanding of periodontal disease pathogenesis and, reciprocally, the study of periodontitis has led to important insights into neutrophil regulation and function. Here, the contributions by our group to this field through interdisciplinary collaboration are discussed. The study of leukocyte adhesion deficiency-associated periodontitis has revealed that the connection of neutrophils with destructive inflammation may involve mechanisms beyond the typical bystander injury dogma. In this regard, neutrophils are required for important immunomodulatory functions and their absence from the periodontium leads to dysregulated overproduction of interleukin-17, which drives inflammatory bone loss. We have also discovered that both the production of neutrophils in the bone marrow and their recruitment to peripheral tissues, including the periodontium, are homeostatically regulated by a secreted protein designated developmental endothelial locus-1. However, developmental endothelial locus-1 expression, and hence developmental endothelial locus-1-dependent homeostasis, declines considerably with aging and contributes to an increased susceptibility to periodontitis in old age. Moreover, our work has mechanistically supported the concept that periodontitis is a dysbiotic disease and we have shown that neutrophils become targets of immune subversion by periodontal bacteria in a manner that promotes dysbiosis. The mechanism involves microbial exploitation of key neutrophil receptors (complement C5a receptor-1 and toll-like receptor-2), leading to crosstalk signaling that uncouples neutrophil-mediated killing (which is impaired) from neutrophil-induced inflammation (which is enhanced). These studies have collectively established new mechanisms governing the protective and destructive functions of neutrophils in periodontitis and offered targeted host-modulation approaches for the treatment of periodontal diseases.