Department of Medicine 3, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
Max Planck Institute for the Science of Light, Erlangen, Germany.
FASEB J. 2019 Jan;33(1):1401-1414. doi: 10.1096/fj.201800752R. Epub 2018 Aug 21.
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 × 10 and 4 × 10 neutrophils/cm. 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.
掌跖角化-牙周病综合征（PLS）的特征为无功能中性粒细胞丝氨酸蛋白酶（NSPs）和原因不明的暴发性牙周炎。在这里，我们研究了正常和 NSP 缺陷的人源和鼠源嗜中性粒细胞的中性粒细胞胞外诱捕（NET）相关聚集和细胞因子/趋化因子的释放/降解。用固体或可溶性 NET 诱导物刺激后，正常中性粒细胞形成聚集物，同时释放和降解细胞因子/趋化因子。随着细胞密度的增加，蛋白水解降解超过了释放。细胞因子/趋化因子的最大输出主要发生在 2×10 和 4×10 个中性粒细胞/cm 的细胞密度之间。对体内中性粒细胞密度的评估表明，在炎症期间这些浓度会超过。与聚集的 NET 相关联赋予了中性粒细胞弹性蛋白酶对α1-抗胰蛋白酶的保护。相比之下，嗜酸性粒细胞不会影响细胞因子/趋化因子的浓度。在 NET 中观察到的炎症介质的蛋白水解降解在掌跖角化-牙周病综合征（PLS）的中性粒细胞中被阻断。总之，中性粒细胞驱动的炎症介质的蛋白水解作用是炎症的内在保护机制。这种负反馈机制的缺失可能是 PLS 中所见的非缓解性牙周炎的原因。-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. 聚集的中性粒细胞胞外诱捕通过细胞因子和趋化因子的蛋白水解以及对抗蛋白酶的保护来解决炎症。
