NOX2-dependent ATM kinase activation dictates pro-inflammatory macrophage phenotype and improves effectiveness to radiation therapy

Autor: Laurent Voisin, Céline Leteur, Fabien Milliat, Eric Deutsch, Qiuji Wu, Eric Solary, Zeinaf Muradova, Haithem Dakhli, Audrey Paoletti, Awatef Allouch, Jean-Luc Perfettini, Filippo Rosselli, Frédéric Law, Mélanie Gauthier, David M. Ojcius, Maxime Thoreau, Elodie Mintet, Nazanine Modjtahedi, Olivier Caron, Isabelle Martins, Céline Mirjolet
Přispěvatelé: Radiothérapie moléculaire (UMR 1030), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut de radioprotection et de sûreté nucléaire [Fontenay-aux-Roses] (IRSN), Ministère de l'économie, de l'industrie et de l'emploi-Ministère de la Défense-Ministère de la santé-Ministère de l'Enseignement Supérieur et de la Recherche Scientifique-Ministère de l'écologie de l'Energie, du Développement durable et de l'Aménagement du territoire, University of California [Merced], University of California, Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Radiothérapie moléculaire [UMR 1030], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] [UNICANCER/CRLCC-CGFL], Institut Jacques Monod [IJM (UMR_7592)], Institut Cochin [IC UM3 (UMR 8104 / U1016)], Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 [CRIStAL], University of California [Merced] [UC Merced], Stabilité Génétique et Oncogenèse [UMR 8200], Apoptose, cancer et immunité [U848], Institut Gustave Roussy (IGR), Systerel, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Laboratoire de Radiopathologie, Génomes et cancer (GC (FRE2939)), Hématopoïèse normale et pathologique, This work was supported by funds from Agence Nationale de la Recherche (ANR-10-IBHU-0001, ANR-10-LABX33 and ANR-11-IDEX-003-01), Electricité de France, Fondation Gustave Roussy, Institut National du Cancer (INCA 9414), NATIXIS, SIDACTION and the French National Agency for Research on AIDS and viral Hepatitis (ANRSH) (to J-LP.), Electricité de France and Fondation Gustave Roussy (to ED). QW is recipient of PhD fellowship of China Scholarship Council. AP and AA are, respectively, recipient of PhD fellowship and post-doc fellowship from Agence Nationale de Recherche sur le Sida et sur les Hépatites (ANRSH). LV and FL are recipient of PhD fellowships from Fondation pour la Recherche Médicale and CIFRE. HD, EM and MT are supported by the Laboratory of Excellence LERMIT with a grant from ANR (ANR-10-LABX-33) under the program ‘Investissements d'Avenir’ ANR-11-IDEX-0003-01. IM is funded by INCA (INCA-DGOS-INSERM 6043). CM work was supported by the ‘Cancéropôle Grand Est’, and the ‘Conseils Régionaux de Bourgogne, de Franche Comté et de Lorraine’., We gratefully acknowledge S Solier, Y Lecluse and S Salome-Desnoulez for technical support., Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre de Recherche en Informatique, Signal et Automatique de Lille (CRIStAL) - UMR 9189 (CRIStAL), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Ecole Centrale de Lille, Ministère de l'écologie de l'Energie, du Développement durable et de l'Aménagement du territoire-Ministère de la santé-Ministère de la Défense-Ministère de l'Enseignement Supérieur et de la Recherche Scientifique-Ministère de l'économie, de l'industrie et de l'emploi
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
[SDV]Life Sciences [q-bio]
Ataxia Telangiectasia Mutated Proteins
Neurodegenerative
Medical and Health Sciences
Mice
0302 clinical medicine
Macrophage
Phosphorylation
ComputingMilieux_MISCELLANEOUS
Cancer
Microscopy
NADPH oxidase
biology
Kinase
Biological Sciences
Flow Cytometry
3. Good health
Cell biology
030220 oncology & carcinogenesis
Signal transduction
Signal Transduction
Biochemistry & Molecular Biology
Fluorescence
Cell Line
03 medical and health sciences
Interferon-gamma
Ataxia Telangiectasia
Rare Diseases
Genetics
Animals
Humans
Molecular Biology
Protein Processing
Original Paper
Macrophages
Post-Translational
Cell Biology
Macrophage Activation
030104 developmental biology
RAW 264.7 Cells
Microscopy
Fluorescence
Apoptosis
biology.protein
Cancer research
Protein Processing
Post-Translational
IRF5
Interferon regulatory factors
Zdroj: Cell Death and Differentiation
Cell Death and Differentiation, Nature Publishing Group, 2017, 24 (9), pp.1632-1644. ⟨10.1038/cdd.2017.91⟩
Cell death and differentiation, vol 24, iss 9
ISSN: 1350-9047
1476-5403
Popis: International audience; Although tumor-associated macrophages have been extensively studied in the control of response to radiotherapy, the molecular mechanisms involved in the ionizing radiation-mediated activation of macrophages remain elusive. Here we show that ionizing radiation induces the expression of interferon regulatory factor 5 (IRF5) promoting thus macrophage activation toward a pro-inflammatory phenotype. We reveal that the activation of the ataxia telangiectasia mutated (ATM) kinase is required for ionizing radiation-elicited macrophage activation, but also for macrophage reprogramming after treatments with γ-interferon, lipopolysaccharide or chemotherapeutic agent (such as cisplatin), underscoring the fact that the kinase ATM plays a central role during macrophage phenotypic switching toward a pro-inflammatory phenotype through the regulation of mRNA level and post-translational modifications of IRF5. We further demonstrate that NADPH oxidase 2 (NOX2)-dependent ROS production is upstream to ATM activation and is essential during this process. We also report that the inhibition of any component of this signaling pathway (NOX2, ROS and ATM) impairs pro-inflammatory activation of macrophages and predicts a poor tumor response to preoperative radiotherapy in locally advanced rectal cancer. Altogether, our results identify a novel signaling pathway involved in macrophage activation that may enhance the effectiveness of radiotherapy through the reprogramming of tumor-infiltrating macrophages.
Databáze: OpenAIRE
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