Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, United States.
Front Immunol. 2021 Feb 17;12:564720. doi: 10.3389/fimmu.2021.564720. eCollection 2021.
Neutrophil granulocytes represent the first line of defense against invading pathogens. In addition to the production of Reactive Oxygen Species, degranulation, and phagocytosis, these specialized cells are able to extrude Neutrophil Extracellular Traps. Extensive work was done to elucidate the mechanism of this special form of cell death. However, the exact mechanisms are still not fully uncovered. Here we demonstrate that the small GTPase Cdc42 is a negative regulator of NET formation in primary human and murine neutrophils. We present a functional role for Cdc42 activity in NET formation that differs from the already described NETosis pathways. We show that Cdc42 deficiency induces NETs independent of the NADPH-oxidase but dependent on protein kinase C. Furthermore, we demonstrate that Cdc42 deficiency induces NETosis through activation of SK-channels and that mitochondria play a crucial role in this process. Our data therefore suggests a mechanistic role for Cdc42 activity in primary human neutrophils, and identify Cdc42 activity as a target to modulate the formation of Neutrophil Extracellular Traps.
中性粒细胞粒细胞代表对抗入侵病原体的第一道防线。除了产生活性氧物质、脱颗粒和吞噬作用外，这些专门的细胞还能够排出中性粒细胞细胞外陷阱。已经做了大量的工作来阐明这种特殊形式的细胞死亡的机制。然而，确切的机制仍未完全揭示。在这里，我们证明小 GTPase Cdc42 是原代人源和鼠源中性粒细胞中 NET 形成的负调节剂。我们展示了 Cdc42 活性在 NET 形成中的功能作用，与已经描述的 NETosis 途径不同。我们表明，Cdc42 缺乏诱导 NET 的形成不依赖于 NADPH 氧化酶，但依赖于蛋白激酶 C。此外，我们证明 Cdc42 缺乏通过激活 SK 通道诱导 NETosis，并且线粒体在这个过程中发挥关键作用。因此，我们的数据表明 Cdc42 活性在原代人中性粒细胞中具有机械作用，并将 Cdc42 活性鉴定为调节中性粒细胞细胞外陷阱形成的靶标。
