Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis.
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.
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany;
C J
CJ
Harbort
Department of Pathology, Federal University of Maranhão, Maranhão, Brazil;
Paulo Vitor
PV
Soeiro-Pereira
Department of Pediatric Pneumology and Immunology, Outpatient Clinic for Primary Immunodeficiencies, Charité Medical School, Berlin, Germany; Labor Berlin, Section for Immunology, Charité-Vivantes GmbH, Berlin, Germany;
Horst
H
von Bernuth
Institute of Cell Biology and Neurobiology, Department of Pediatric Neurology, and Sozialpädiatrisches Zentrum (SPZ), Charité-Universitätsmedizin Berlin, Berlin, Germany;
Angela M
AM
Kaindl
Department of Pediatrics, Federal University of São Paulo Medical School, São Paulo, Brazil;
Beatriz Tavares
BT
Costa-Carvalho
Department of Immunology, Institute of Biomedical Sciences-University of São Paulo, São Paulo, Brazil;
Antonio
A
Condino-Neto
Division of Immunology, University Children's Hospital, and Children's Research Centre, Swiss Center for Regenerative Medicine, Center for Applied Biotechnology and Molecular Medicine, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland; and.
Janine
J
Reichenbach
Department of Pediatrics, University Hospital TU Dresden, Dresden, Germany.
Joachim
J
Roesler
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany;
Arturo
A
Zychlinsky
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany;
Borko
B
Amulic
D017209:Apoptosis / Q000502:physiology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D015153:Blotting, Western; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D009504:Neutrophils / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D016897:Respiratory Burst / Q000502:physiology*
D016207:Cytokines; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins