Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis

C J Harbort, Paulo Vitor Soeiro-Pereira, Horst von Bernuth, Angela M Kaindl, Beatriz Tavares Costa-Carvalho, Antonio Condino-Neto, Janine Reichenbach, Joachim Roesler, Arturo Zychlinsky, Borko Amulic

Research output: Contribution to journalArticle (Academic Journal)peer-review

43 Citations (Scopus)
263 Downloads (Pure)

Abstract

Neutrophils play an essential role in the initial stages of inflammation by balancing pro- and antiinflammatory signals. Among these signals are the production of proinflammatory cytokines and the timely initiation of antiinflammatory cell death via constitutive apoptosis. Here we identify ataxia-telangiectasia mutated (ATM) kinase as a modulator of these neutrophil functions. Ataxia-telangiectasia (AT) is a pleiotropic multisystem disorder caused by mutations in the gene-encoding ATM, a master regulator of the DNA damage response. In addition to progressive neurodegeneration and high rates of cancer, AT patients have numerous symptoms that can be linked to chronic inflammation. We report that neutrophils isolated from patients with AT overproduce proinflammatory cytokines and have a prolonged lifespan compared with healthy controls. This effect is partly mediated by increases in activation of p38 MAP kinase. Furthermore, we show that the oxidative burst, catalyzed by nicotinamide adenine dinucleotide phosphate oxidase, can activate ATM in neutrophils. Finally, activation of ATM and DNA damage signaling suppress cytokine production and can abrogate the overproduction of IL-8 in ROS-deficient cells. This reveals a novel mechanism for the regulation of cytokine production and apoptosis, establishing DNA damage as a downstream mediator of immune regulation by reactive oxygen species. We propose that deficiencies in the DNA damage response, like deficiencies in the oxidative burst seen in chronic granulomatous disease, could lead to pathologic inflammation.

Original languageEnglish
Pages (from-to)2842-2851
Number of pages10
JournalBlood
Volume126
Issue number26
Early online date21 Oct 2015
DOIs
Publication statusPublished - 24 Dec 2015

Keywords

  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • Blotting, Western
  • Cell Separation
  • Cytokines
  • Enzyme Activation
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Neutrophils
  • Real-Time Polymerase Chain Reaction
  • Respiratory Burst
  • Journal Article
  • Research Support, Non-U.S. Gov't

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