Papillon-Lefèvre syndrome (PLS) is characterized by nonfunctional neutrophil serine
proteases (NSPs) and fulminant periodontal inflammation of unknown cause. Here we
investigated neutrophil extracellular trap (NET)-associated aggregation and cytokine/chemokine-release/degradation
by normal and NSP-deficient human and mouse granulocytes. Stimulated with solid or
soluble NET inducers, normal neutrophils formed aggregates and both released and degraded
cytokines/chemokines. With increasing cell density, proteolytic degradation outweighed
release. Maximum output of cytokines/chemokines occurred mostly at densities between
2 × 107 and 4 × 107 neutrophils/cm3. Assessment of neutrophil density in vivo showed
that these concentrations are surpassed during inflammation. Association with aggregated
NETs conferred protection of neutrophil elastase against α1-antitrypsin. In contrast,
eosinophils did not influence cytokine/chemokine concentrations. The proteolytic degradation
of inflammatory mediators seen in NETs was abrogated in Papillon-Lefèvre syndrome
(PLS) neutrophils. In summary, neutrophil-driven proteolysis of inflammatory mediators
works as a built-in safeguard for inflammation. The absence of this negative feedback
mechanism might be responsible for the nonresolving periodontitis seen in PLS.-Hahn,
J., Schauer, C., Czegley, C., Kling, L., Petru, L., Schmid, B., Weidner, D., Reinwald,
C., Biermann, M. H. C., Blunder, S., Ernst, J., Lesner, A., Bäuerle, T., Palmisano,
R., Christiansen, S., Herrmann, M., Bozec, A., Gruber, R., Schett, G., Hoffmann, M.
H. Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of
cytokines and chemokines and protection from antiproteases.