Proteases,neutrophils, and periodontitis: the NET effect

Neutrophils exert potent antimicrobial activities in their role as first-line cellular defenders against infection. The synergistic and collective actions of oxidants and granule proteins, including serine proteases, support the microbial killing in phagosomes, where most neutrophil-mediated antimicrobial action occurs. In addition to phagocytosis, specific stimuli prompt neutrophils to extrude a matrix of DNA, histones, and granule proteins to produce neutrophil extracellular traps (NETs), which can trap microbes. Mice lacking the serine proteases necessary for NET production are more susceptible to infection, an observation suggesting that functional NETs are required for host protection. In this issue of the JCI, Sørensen and colleagues characterize neutrophils from a patient with Papillon-Lefèvre syndrome. The patient has an inactivating mutation in the gene encoding dipeptidyl peptidase I, resulting in neutrophils lacking elastase, a serine protease required for NET production. Despite the inability to form NETS, neutrophils from this patient killed pathogens in vitro, and the patient did not exhibit evidence of an increased propensity toward bacterial infections. Together, these results suggest that proteases in human neutrophils are dispensable for protection against bacterial infection and that the ability to generate NETs in vitro does not compromise host defense. He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all. —William Osler, MDThe desire to quell patients’ suffering drives the quest to elucidate the mechanisms that underlie disease pathogenesis. Patients not only provide incentive for biomedical pursuits, but also redirect our notions about a particular disease when we drift off course. In this issue, Sørensen et al. describe the genetic abnormality in a young female with Papillon-Lefèvre syndrome (PLS) (1), a rare autosomal disorder also known as keratosis palmoplantaris with periodontopathia (2). The patient was found to have a mutation in CTSC, which encodes dipeptidyl peptidase I (DPPI), a lysosomal cysteine proteinase that converts inactive precursors of granule serine proteases into active enzymes (3). DPPI levels are especially high in human neutrophils, alveolar macrophages, and their progenitors (3). Moreover, as demonstrated by Sørensen et al., DPPI-deficient neutrophils lack elastase, cathepsin G, proteinase 3 (PR3), and neutrophil serine protease 4 (NSP4), four serine proteases normally housed within azurophil granules. Consequently, it would be predicted that the absence of these DPPI-dependent serine proteases would undermine one or more critical neutrophil activities.