Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases

Jonas Hahn , Christine Schauer , Christine Czegley , Lasse Kling , Lenka Petru , Benjamin Schmid , Daniela Weidner , Christiane Reinwald , Mona H. C. Biermann , Stefan Blunder , Jürgen Ernst , Adam Lesner , Tobias Bäuerle , Ralf Palmisano , Silke Christiansen , Martin Herrmann , Aline Bozec , Robert Gruber , Georg Schett , Markus H. Hoffmann

Abstract

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.
Publication typeIn press (online first, early view)
Author Jonas Hahn
Jonas Hahn,,
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, Christine Schauer
Christine Schauer,,
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, Christine Czegley
Christine Czegley,,
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, Lasse Kling
Lasse Kling,,
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, Lenka Petru
Lenka Petru,,
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, Benjamin Schmid
Benjamin Schmid,,
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, Daniela Weidner
Daniela Weidner,,
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, Christiane Reinwald
Christiane Reinwald,,
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, Mona H. C. Biermann
Mona H. C. Biermann,,
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, Stefan Blunder
Stefan Blunder,,
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et al.`
Journal seriesFASEB Journal, ISSN 0892-6638, (A 35 pkt)
Issue year2018
Noonline first
DOIDOI:10.1096/fj.201800752R
Languageen angielski
Score (nominal)40
ScoreMinisterial score = 35.0, 28-10-2018, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 28-10-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 5.498 (2) - 2016=5.435 (5)
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