Amini Poorya, Stojkov Darko, Wang Xiaoliang, Wicki Simone, Kaufmann Thomas, Wong Wendy Wei-Lynn, Simon Hans-Uwe, Yousefi Shida
Institute of Pharmacology, University of Bern, Bern, Switzerland.
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Eur J Immunol. 2016 Jan;46(1):178-84. doi: 10.1002/eji.201545615. Epub 2015 Dec 2.
The importance of neutrophil extracellular traps (NETs) in innate immunity is well established but the molecular mechanisms responsible for their formation are still a matter of scientific dispute. Here, we aim to characterize a possible role of the receptor-interacting protein kinase 3 (RIPK3) and the mixed lineage kinase domain-like (MLKL) signaling pathway, which are known to cause necroptosis, in NET formation. Using genetic and pharmacological approaches, we investigated whether this programmed form of necrosis is a prerequisite for NET formation. NETs have been defined as extracellular DNA scaffolds associated with the neutrophil granule protein elastase that are capable of killing bacteria. Neither Ripk3-deficient mouse neutrophils nor human neutrophils in which MLKL had been pharmacologically inactivated, exhibited abnormalities in NET formation upon physiological activation or exposure to low concentrations of PMA. These data indicate that NET formation occurs independently of both RIPK3 and MLKL signaling.
中性粒细胞胞外诱捕网（NETs）在固有免疫中的重要性已得到充分证实，但其形成的分子机制仍是科学争议的焦点。在此，我们旨在阐明受体相互作用蛋白激酶3（RIPK3）和混合谱系激酶结构域样蛋白（MLKL）信号通路（已知可引发坏死性凋亡）在NET形成中可能发挥的作用。我们采用遗传学和药理学方法，研究这种程序性坏死形式是否为NET形成的先决条件。NETs被定义为与中性粒细胞颗粒蛋白弹性蛋白酶相关的细胞外DNA支架，能够杀灭细菌。无论是Ripk3基因敲除小鼠的中性粒细胞，还是经药理学方法使MLKL失活的人类中性粒细胞，在生理激活或暴露于低浓度佛波酯（PMA）时，NET形成均未出现异常。这些数据表明，NET的形成独立于RIPK3和MLKL信号通路。
