Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis

Harbort, Christopher J.; Soeiro-Pereira, Paulo Vítor; Bernuth, Horst von; Kaindl, Angela M.; Costa‐Carvalho, Beatriz Tavares; Condino‐Neto, Antônio; Reichenbach, Janine; Roesler, Joachim; Zychlinsky, Arturo; Amulic, Borko

doi:10.1182/blood-2015-05-645424

Cited by 63 publications

(59 citation statements)

References 52 publications

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“…Both cell types lacked DNA-PK CS protein expression; however, unlike in monocytes the DNA damage response kinases ATR and ATM were also not detectable in neutrophilic granulocytes. This contrasts with a previous report where ATM was activated and pATM was detected after IR or PMA treatment [30]. Furthermore, the DSB marker γH2AX was also not detectable in dose- and time-response experiments after treatment with IR, which is compatible with the observed lack of DNA damage-dependent kinases in our samples.…”

Section: Discussioncontrasting

confidence: 57%

“…It was also reported that PMA-treated blood cells displayed phosphorylation of ATM and H2AX in granulocytes, monocytes and lymphocytes [29]. Another study found phosphorylated ATM and H2AX (γH2AX) in neutrophils after NADPH oxidase activation and IR [30]. In view of these rather controversial results we analysed DNA repair protein expression and DNA repair capacity in granulocytes after exposure to ROS and IR.…”

Section: Discussionmentioning

confidence: 99%

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Compromised DNA Repair and Signalling in Human Granulocytes

Ponath¹,

Heylmann²,

Haak³

et al. 2018

J Innate Immun

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In previous studies, we showed impaired DNA repair in human monocytes. Here, we addressed the question of whether human neutrophilic granulocytes that arise from the same precursor as monocytes exhibit a similar phenotype and are impaired in repairing their DNA. We show that neutrophilic granulocytes isolated from peripheral blood display a lack of the same repair proteins that are missing in monocytes and do not show repair of their DNA when damaged by ionising radiation (IR) or chemical ROS. Contrary to T cells, we observed no decline in the number of single-strand breaks following γ-radiation. Also, granulocytes did not show γH2AX foci formation while T cells and peripheral blood lymphocytes (PBL) responded. In comparison to PBL, XRCC1, PARP-1 and ligase III were not expressed and there was also no discernible signal for key damage response proteins ATM, ATR and DNA-PK_CS as well as γH2AX in neutrophils. Time course and dose-response experiments confirmed the absence of H2AX phosphorylation after radiation treatment although an accumulation of double-strand breaks was detected in the neutral Comet assay. Overall, the data indicate that terminally differentiated neutrophilic granulocytes in the peripheral blood display strong downregulation of DNA repair and DNA damage response factors, which should be taken into account if studies with whole peripheral blood containing granulocytes are performed, causing a significant intra-experimental variation in the cellular repair capacity.

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Compromised DNA Repair and Signalling in Human Granulocytes

Ponath¹,

Heylmann²,

Haak³

et al. 2018

J Innate Immun

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“…7A), and observed an increase as previously reported by Harbort et al [32]. In addition KU-55933, a specific inhibitor of ATM decreased the phospho-ATM of neutrophils in a concentration dependent way (Fig.…”

Section: Resultssupporting

confidence: 88%

Down-regulation of NOX2 activity in phagocytes mediated by ATM-kinase dependent phosphorylation

Beaumel

Picciocchi

Debeurme

et al. 2017

Free Radical Biology and Medicine

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NADPH oxidases (NOX) have many biological roles, but their regulation to control production of potentially toxic ROS molecules remains unclear. A previously identified insertion sequence of 21 residues (called NIS) influences NOX activity, and its predicted flexibility makes it a good candidate for providing a dynamic switch controlling the NOX active site. We constructed NOX2 chimeras in which NIS had been deleted or exchanged with those from other NOXs (NIS1, 3 and 4). All contained functional heme and were expressed normally at the plasma membrane of differentiated PLB-985 cells. However, NOX2-ΔNIS and NOX2-NIS1 had neither NADPH-oxidase nor reductase activity and exhibited abnormal translocation of p47phox and p67phox to the phagosomal membrane. This suggested a functional role of NIS. Interestingly after activation, NOX2-NIS3 cells exhibited superoxide overproduction compared with wild-type cells. Paradoxically, the Vmax of purified unstimulated NOX2-NIS3 was only one-third of that of WT-NOX2. We therefore hypothesized that post-translational events regulate NOX2 activity and differ between NOX2-NIS3 and WT-NOX2. We demonstrated that Ser486, a phosphorylation target of ataxia telangiectasia mutated kinase (ATM kinase) located in the NIS of NOX2 (NOX2-NIS), was phosphorylated in purified cytochrome b558 after stimulation with phorbol 12-myristate-13-acetate (PMA). Moreover, ATM kinase inhibition and a NOX2 Ser486Ala mutation enhanced NOX activity whereas a Ser486Glu mutation inhibited it. Thus, the absence of Ser486 in NIS3 could explain the superoxide overproduction in the NOX2-NIS3 mutant. These results suggest that PMA-stimulated NOX2-NIS phosphorylation by ATM kinase causes a dynamic switch that deactivates NOX2 activity. We hypothesize that this downregulation is defective in NOX2-NIS3 mutant because of the absence of Ser486.

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“…It has recently been reported that stimulated neutrophils generate a burst of ROS that induce DNA damage signaling in activated neutrophils and macrophages, suppressing cytokine production and inducing apoptosis. If the DNA damage reparative systems are effective cells will survive, otherwise they will become apoptotic and die [35][36][37].…”

Section: Cellular Apoptosis Induction and Regulation Pathwaysmentioning

confidence: 99%

Role of Neutrophils Apoptosis in Osteomyelitis Pathogenesis

Asensi¹,

Collazos²,

Valle-Garay³

2017

Clin Microbiol

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EditorialOsteomyelitis is a bone infection characterized by progressive inflammatory destruction of the infected bone and new apposition of bone at the site of infection. In adults, osteomyelitis is usually a complication of open wounds due to fractures, surgery, or both, with or without the presence of foreign bodies such as prosthetic devices. In fact, it is estimated that about 0.4 to 7% of trauma and orthopaedic interventions are complicated by osteomyelitis [1][2][3][4][5][6].Bone infections can also be the result of bacteraemia, mostly in children and in elderly patients, in whom the infection involves mainly the axial skeleton. The microorganism most frequently isolated in both post-traumatic and haematogenous cases is Staphylococcus aureus.Osteomyelitis constitutes a difficult-to-treat infection, with high rates of recurrence of about 20-30% despite appropriate medical and surgical therapies, causing significant morbidity and mortality [7][8][9][10][11][12][13].Much attention has been dedicated to improving the medical and surgical treatments of osteomyelitis, but little progress has been made toward understanding its pathogenesis. It is clear that it is multifactorial and influenced mainly by local factors related to the bone lesion and microorganisms inoculated into the bone, but inherited factors and cell immunity dysfunctions could play some role as well [14][15][16][17][18][19][20][21][22][23][24][25][26].

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Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis

Abstract: Key Points Activation of ATM kinase modulates neutrophil functions and is dependent on the oxidative burst. Neutrophils from ataxia telangiectasia patients overproduce inflammatory cytokines and have a prolonged lifespan.

Cited by 63 publications

References 52 publications

Compromised DNA Repair and Signalling in Human Granulocytes

Compromised DNA Repair and Signalling in Human Granulocytes

Down-regulation of NOX2 activity in phagocytes mediated by ATM-kinase dependent phosphorylation

Role of Neutrophils Apoptosis in Osteomyelitis Pathogenesis

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