The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils

D’Cruz, Akshay A.; Speir, Mary; Bliss-Moreau, Meghan; Dietrich, Sylvia; Wang, Shu; Chen, Alyce A.; Gavillet, Mathilde; Al-Obeidi, Arshed; Lawlor, Kate E.; Vince, James E.; Kelliher, Michelle A.; Hakem, Razqallah; Pasparakis, Manolis; Williams, David A.; Ericsson, Maria; Croker, Ben A.

doi:10.1126/scisignal.aao1716

Cited by 66 publications

(87 citation statements)

References 71 publications

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“…Prior study indicated that the necroptotic cell death effector MLKL phosphorylation forming a polymer which translocated from the cytoplasm to the plasma membrane to perforation (45)(46)(47)(48). Prior study indicated that MLKL phosphorylation could stimulate downstream NADPH oxidase-independent ROS production, breakdown of the nuclear membrane, and induce NETs formation (49). So we speculate that Nec-1 suppresses the release of NETs by inhibiting phosphorylation and perforation of MLKL.…”

Section: Discussionmentioning

confidence: 74%

Necrostatin-1 Ameliorates Neutrophilic Inflammation in Asthma by Suppressing MLKL Phosphorylation to Inhibiting NETs Release

et al. 2020

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Neutrophilic inflammation occurs during asthma exacerbation, and especially, in patients with steroid-refractory asthma, but the underlying mechanisms are poorly understood. Recently, a significant accumulation of neutrophil extracellular traps (NETs) in the airways of neutrophilic asthma has been documented, suggesting that NETs may play an important role in the pathogenesis. In this study, we firstly demonstrated that NETs could induce human airway epithelial cell damage in vitro. In a mouse asthmatic model of neutrophil-dominated airway inflammation, we found that NETs were markedly increased in bronchoalveolar lavage (BAL), and the formation of NETs exacerbated the airway inflammation. Additionally, a small-molecule drug necrostatin-1 (Nec-1) shown to inhibit NETs formation was found to alleviate the neutrophil-dominated airway inflammation. Nec-1 reduced total protein concentration, myeloperoxidase activity, and the levels of inflammatory cytokines in BAL. Finally, further experiments proved that the inhibition of Nec-1 on NETs formation might be related to its ability to inhibiting mixed lineage kinase domain-like (MLKL) phosphorylation and perforation. Together, these results document that NETs are closely associated with the pathogenesis of neutrophilic asthma and inhibition of the formation of NETs by Nec-1 may be a new therapeutic strategy to ameliorate neutrophil-dominated airway inflammation.

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Section: Discussionmentioning

confidence: 74%

Necrostatin-1 Ameliorates Neutrophilic Inflammation in Asthma by Suppressing MLKL Phosphorylation to Inhibiting NETs Release

et al. 2020

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“…Another pore-forming protein MLKL (not related to gasdermins) is activated by RIP kinases during necroptosis. Activation of MLKL in neutrophils can also lead to the release of NETs [ 11 - 13 ].…”

Section: Mechanisms Of Netosismentioning

confidence: 99%

“…The signaling mechanisms of NETosis may include activation of phosphoinositide-3-kinase (PI3K) [ 9 ], which also controls the autophagy induction, but assembly of autophagosomes is not required for NETosis [ 10 ]. The pathways leading to NETosis and necroptosis can be especially closely intertwined [ 11 - 13 ]. For a long time, it was believed that mitochondria do not play a significant role in the functioning of neutrophils, since their content in these cells is low, energy supply is supported by glycolysis, and NADPH oxidase is the main source of ROS.…”

Section: Introductionmentioning

confidence: 99%

NETosis: Molecular Mechanisms, Role in Physiology and Pathology

Vorobjeva

Chernyak

2020

Biochemistry Moscow

242

227

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NETosis is a program for formation of neutrophil extracellular traps (NETs), which consist of modified chromatin decorated with bactericidal proteins from granules and cytoplasm. Various pathogens, antibodies and immune complexes, cytokines, microcrystals, and other physiological stimuli can cause NETosis. Induction of NETosis depends on reactive oxygen species (ROS), the main source of which is NADPH oxidase. Activation of NADPH oxidase depends on increase in the concentration of Ca 2+ in the cytoplasm and in some cases on the generation of ROS in mitochondria. NETosis includes release of the granule components into the cytosol, modification of histones leading to chromatin decondensation, destruction of the nuclear envelope, as well as formation of pores in the plasma membrane. In this review, basic mechanisms of NETosis, as well as its role in the pathogenesis of some diseases including COVID-19 are discussed.

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“…In agreement with the observation that death effector proteins drive NET expulsion, a recent study likewise reported that MLKL, the death effector in the necroptosis pathway, promotes NETosis in necroptotic neutrophils. Mechanistically, MLKL‐driven plasma membrane pores promote calcium influx, PAD4 activation, and NET release 112 . Importantly, Pad4‐ deficient neutrophils fail to undergo NETosis in necroptotic neutrophils, while PAD4 is dispensable for non‐canonical NETosis.…”

Section: Programmed Cell Death During Bacterial Infectionmentioning

confidence: 99%

Cross talk between intracellular pathogens and cell death

Demarco

Chen

Brož

2020

Immunological Reviews

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Infections with bacterial pathogens often results in the initiation of programmed cell death as part of the host innate immune defense, or as a bacterial virulence strategy. Induction of host cell death is controlled by an elaborate network of innate immune and cell death signaling pathways and manifests in different morphologically and functionally distinct forms of death, such as apoptosis, necroptosis, NETosis and pyroptosis. The mechanism by which host cell death restricts bacterial replication is highly cell‐type and context depended, but its physiological importance is highlighted the diversity of strategies bacterial pathogens use to avoid induction of cell death or to block cell death signaling pathways. In this review, we discuss the latest insights into how bacterial pathogens elicit and manipulate cell death signaling, how different forms of cell death kill or restrict bacteria and how cell death and innate immune pathway cross talk to guard against pathogen‐induced inhibition of host cell death.

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The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils

Cited by 66 publications

References 71 publications

Necrostatin-1 Ameliorates Neutrophilic Inflammation in Asthma by Suppressing MLKL Phosphorylation to Inhibiting NETs Release

Necrostatin-1 Ameliorates Neutrophilic Inflammation in Asthma by Suppressing MLKL Phosphorylation to Inhibiting NETs Release

NETosis: Molecular Mechanisms, Role in Physiology and Pathology

Cross talk between intracellular pathogens and cell death

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