Abstract
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.
Highlights
Since the discovery of a novel cell death mechanism in 1996 that was different from apoptosis or necrosis, considerable effort was made to further characterize this phenomenon (1)
Since the first description of the formation of Neutrophil Extracellular Traps (NETs) it was demonstrated that various stimuli, such as lipopolysaccharides (LPS), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNFα) and pathogens can induce the extrusion of DNA in neutrophil granulocytes (4)
To elucidate the role of Cdc[42] activity in the formation of NETs, neutrophil granulocytes were treated with PMA or with the Cdc[42] inhibitor casin or a combination of PMA and casin
Summary
Since the discovery of a novel cell death mechanism in 1996 that was different from apoptosis or necrosis, considerable effort was made to further characterize this phenomenon (1). In 2004, Brinkmann reported a form of neutrophil cell death, leading to DNA extrusion during bacterial infection (2). This novel form of programmed cell death was termed NETosis in 2007 (3). Since the first description of the formation of Neutrophil Extracellular Traps (NETs) it was demonstrated that various stimuli, such as lipopolysaccharides (LPS), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNFα) and pathogens can induce the extrusion of DNA in neutrophil granulocytes (4). NETs are composed of chromosomal DNA that is associated with nuclear histones, granular antimicrobial proteins, and some cytoplasmic proteins (6–10). The extruded DNA appears as a web like structure that is made of long DNA fibers, perfectly suitable to bind and trap pathogens. Diverse proteins adhere to the DNA, including histones as well as over
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