Aging‐related Atg5 defect impairs neutrophil extracellular traps formation

Xu, Fei; Zhang, Chengmi; Zou, Zui; Fan, Erica K.; Chen, Linsong; Li, Yuehua; Billiar, Timothy R.; Wilson, Mark A.; Shi, Xueyin; Fan, Jie

doi:10.1111/imm.12740

Cited by 66 publications

(66 citation statements)

References 47 publications

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“…Previously published work pointed to the possibility that NET formation required autophagy . It should be noted that these studies used pharmacological inhibitors to block class III PI3K in order to stop the initiation of autophagosome formation.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study, it was suggested that neutrophils from older mice exhibit decreased expression levels of ATG5 and reduced levels of autophagy. Such neutrophils also had a reduced capacity to generate NETs and the authors implied that autophagy could regulate NET formation …”

Section: Discussionmentioning

confidence: 99%

“…Moreover, controversial findings have been reported regarding the effect of mammalian target of rapamycin on the kinetics of NET formation; both inhibitory and potentiating effects have been observed . Very recently it has been suggested that ageing‐related ATG5 defects might impair NET formation …”

Section: Introductionmentioning

confidence: 99%

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Neither eosinophils nor neutrophils require ATG5‐dependent autophagy for extracellular DNA trap formation

et al. 2017

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The importance of extracellular traps (ETs) in innate immunity is well established, but the molecular mechanisms responsible for their formation remain unclear and in scientific dispute. ETs have been defined as extracellular DNA scaffolds associated with the granule proteins of eosinophils or neutrophils. They are capable of killing bacteria extracellularly. Based mainly on results with phosphoinositide 3-kinase (PI3K) inhibitors such as 3-methyladenine (3-MA) and wortmannin, which are commonly used to inhibit autophagy, several groups have reported that autophagy is required for neutrophil extracellular trap (NET) formation. We decided to investigate this apparent dependence on autophagy for ET release and generated genetically modified mice that lack, specifically in eosinophils or neutrophils, autophagy-related 5 (Atg5), a gene encoding a protein essential for autophagosome formation. Interestingly, neither eosinophils nor neutrophils from Atg5-deficient mice exhibited abnormalities in ET formation upon physiological activation or exposure to low concentrations of PMA, although we could confirm that human and mouse eosinophils and neutrophils, after pre-treatment with inhibitors of class III PI3K, show a block both in reactive oxygen species (ROS) production and in ET formation. The so-called late autophagy inhibitors bafilomycin A1 and chloroquine, on the other hand, were without effect. These data indicate that ET formation occurs independently of autophagy and that the inhibition of ROS production and ET formation in the presence of 3-MA and wortmannin is probably owing to their additional ability to block the class I PI3Ks, which are involved in signalling cascades initiated by triggers of ET formation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Neither eosinophils nor neutrophils require ATG5‐dependent autophagy for extracellular DNA trap formation

et al. 2017

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“…The first genetic evidence illustrated that silencing of Atg5 in a neutrophil-like human cell line infected with adherent-invasive Escherichia coli blocked NET formation [103]. Recently, diminished Atg5 expression due to aging was also shown to reduce the capacity of neutrophils to form NETs [106][107][108]. In apparent contrast, Atg5-knockout mouse neutrophils had reduced autophagic activity but normal capacity to release extracellular DNA [109].…”

Section: Pathways Of Net Formationmentioning

confidence: 99%

To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps

et al. 2019

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Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro-and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.

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“…Recently Atg5 aging-related defects have been linked to an impaired NET formation. In this sense, the interference at the level of autophagy-promoted NETs may be a promising as a therapeutic target for chronic PD due to its link with aging (Xu et al, 2017). Autophagy can be a contributor factor in the onset of NETosis, but superoxide is not per se required for the induction of PNMs autophagy in vitro (Fuchs et al, 2007).…”

Section: Chaperonesmentioning

confidence: 99%

Autophagy in periodontal disease: Evidence from a literature review

Lorenzo-Pouso¹,

Castelo‐Baz²,

Pérez‐Sayáns³

et al. 2019

Archives of Oral Biology

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Objective: To summarize evidence and data in relation to the implications of autophagy in periodontal disease (PD) and describe potential nutraceuticals or pharmaceuticals able to modulate this subtype of cell death. Design: Literature searches of different electronic databases (Medline via PubMed, SCOPUS, Web of Science, and EMBASE) using appropriate keywords (e.g. periodontal disease, periodontitis, alveolar bone loss, periodontal infection, tooth loss, autophagy, programmed cell death, type 2 cell death) were performed. Then, a comprehensive literature review of the current understanding of this link was elaborated. Results: Autophagy plays a pivotal role in PD and it seems that its regulation may be an interesting avenue for future periodontal research according to several in vivo and in vitro reports. Conclusion: Nowadays research has ascertained the role of autophagy in PD, specially its role in the host defence against periodontal disease drivers. A bulk of research has recognized several pharmaceuticals and nutraceuticals that can potentially modulate this kind of cell death and serve as useful therapies. However, further research is warranted in order to reach a clinical translation, which could be of help in the discovery of novel host modulation therapies for PD.

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Aging‐related Atg5 defect impairs neutrophil extracellular traps formation

Cited by 66 publications

References 47 publications

Neither eosinophils nor neutrophils require ATG5‐dependent autophagy for extracellular DNA trap formation

Neither eosinophils nor neutrophils require ATG5‐dependent autophagy for extracellular DNA trap formation

To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps

Autophagy in periodontal disease: Evidence from a literature review

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