Akt is essential to induce NADPH-dependent NETosis and to switch the neutrophil death to apoptosis

Douda, David N.; Yip, Lily; Khan, Meraj A.; Grasemann, Hartmut; Palaniyar, Nades

doi:10.1182/blood-2013-09-526707

Cited by 120 publications

(152 citation statements)

References 10 publications

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“…Although p38 was activated in both types of NETosis, p38 inhibitor SB202190 did not inhibit NETosis. Consistent with our previous report (15), we show that Akt is required for NOX-dependent NETosis (Fig. 3 and Fig.…”

Section: Discussionsupporting

confidence: 81%

“…Much of our current understanding of the molecular mechanisms that govern the NOX-dependent pathway results from studies using phorbol 12-myristate 13-acetate (PMA) (14)(15)(16). The use of pharmacological agonists such as PMA as the NOX-dependent NET inducer is attractive due to its ability to uniformly activate the cells in culture.…”

Section: Resultsmentioning

confidence: 99%

“…2 and 4). During NOX-dependent NETosis, production of NOX-dependent ROS is required for the activation of ERK, Akt, and p38 (15,16). ERK has been implicated as the major kinase involved in NOXdependent NETosis (14,16).…”

Section: Discussionmentioning

confidence: 99%

“…We next sought to determine differences in the signaling pathways that are activated in NOX-dependent and -independent NETosis. Number of key kinases such as ERK (14), Akt (15), and p38 (16) have been shown to be activated in PMA-induced NETosis. Thus, we next assessed differences in the activation of these kinases during PMA-and A23187-induced NETosis over a 120-min period following the activation of neutrophils (Fig.…”

Section: Differential Activation Of Kinases In Nox-dependent and -Indmentioning

confidence: 99%

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SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx

Douda¹,

Khan²,

Grasemann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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485

614

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Neutrophils cast neutrophil extracellular traps (NETs) to defend the host against invading pathogens. Although effective against microbial pathogens, a growing body of literature now suggests that NETs have negative impacts on many inflammatory and autoimmune diseases. Identifying mechanisms that regulate the process termed “NETosis” is important for treating these diseases. Although two major types of NETosis have been described to date, mechanisms regulating these forms of cell death are not clearly established. NADPH oxidase 2 (NOX2) generates large amounts of reactive oxygen species (ROS), which is essential for NOX-dependent NETosis. However, major regulators of NOX-independent NETosis are largely unknown. Here we show that calcium activated NOX-independent NETosis is fast and mediated by a calcium-activated small conductance potassium (SK) channel member SK3 and mitochondrial ROS. Although mitochondrial ROS is needed for NOX-independent NETosis, it is not important for NOX-dependent NETosis. We further demonstrate that the activation of the calcium-activated potassium channel is sufficient to induce NOX-independent NETosis. Unlike NOX-dependent NETosis, NOX-independent NETosis is accompanied by a substantially lower level of activation of ERK and moderate level of activation of Akt, whereas the activation of p38 is similar in both pathways. ERK activation is essential for the NOX-dependent pathway, whereas its activation is not essential for the NOX-independent pathway. Despite the differential activation, both NOX-dependent and -independent NETosis require Akt activity. Collectively, this study highlights key differences in these two major NETosis pathways and provides an insight into previously unknown mechanisms for NOX-independent NETosis.

show abstract

Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Differential Activation Of Kinases In Nox-dependent and -Indmentioning

confidence: 99%

See 2 more Smart Citations

SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx

Douda¹,

Khan²,

Grasemann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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485

614

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show abstract

“…Akt has been described as a bona fide molecular switch that regulates the type of cell death that neutrophils develop, as activation (phosphorylation) of this molecule shifts cell death from apoptosis to NETosis (31). Other kinases such as ERK are activated during NETosis (32).…”

Section: Resultsmentioning

confidence: 99%

A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity

et al. 2017

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Encountering and Wrestling: Neutrophils Recognize and Defensively Degrade Graphene Oxide

Huang

Liu

et al. 2021

Adv Healthcare Materials

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The boosting exploitation of graphene oxide (GO) increases exposure risk to human beings. However, as primary defender in the first immune line, neutrophils' mechanism of defensive behavior toward GO remains unclear. Herein, we discovered that neutrophils recognize and defensively degrade GO in a lateral dimension dependent manner. The micrometer-sized GO (mGO) induces NETosis by releasing neutrophil extracellular traps (NETs), while nanometer-sized GO (nGO) elicits neutrophil degranulation. The two neutrophils' defensive behaviors are accompanied with generation of reactive oxygen species and activation of p-ERK and p-Akt kinases. However, mGO-induced NETosis is NADPH oxidase (NOX)-independent while nGO-triggered degranulation is NOX-dependent. Furthermore, myeloperoxidase (MPO) is determinant mediator despite distinct neutrophil phenotypes. Neutrophils release NETs comprising of MPO upon activated with mGO, while MPO is secreted via nGO-induced degranulation. Moreover, the binding energy between MPO and GO is calculated to be 69.8728 kJ mol −1 , indicating that electrostatic interactions mainly cause the spontaneous binding process. Meanwhile, the central enzymatic biodegradation occurs at oxygenic active sites and defects on GO. Mass spectrometry analysis deciphers the degradation products are biocompatible molecules like flavonoids and polyphenols. This study provides fundamental evidence and practical guidance for nanotechnology based on GO, including vaccine adjuvant, implantable devices, and energy storage.

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Akt is essential to induce NADPH-dependent NETosis and to switch the neutrophil death to apoptosis

Cited by 120 publications

References 10 publications

SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx

SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx

A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity

Encountering and Wrestling: Neutrophils Recognize and Defensively Degrade Graphene Oxide

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