NOX2-dependent ATM kinase activation dictates pro-inflammatory macrophage phenotype and improves effectiveness to radiation therapy.
Fiche publication
Date publication
juin 2017
Journal
Cell death and differentiation
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MIRJOLET Céline
Tous les auteurs :
Wu Q, Allouch A, Paoletti A, Leteur C, Mirjolet C, Martins I, Voisin L, Law F, Dakhli H, Mintet E, Thoreau M, Muradova Z, Gauthier M, Caron O, Milliat F, Ojcius DM, Rosselli F, Solary E, Modjtahedi N, Deutsch E, Perfettini JL
Lien Pubmed
Résumé
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.Cell Death and Differentiation advance online publication, 2 June 2017; doi:10.1038/cdd.2017.91.
Mots clés
Animals, Ataxia Telangiectasia Mutated Proteins, metabolism, Cell Line, Flow Cytometry, Humans, Interferon-gamma, metabolism, Macrophage Activation, radiation effects, Macrophages, metabolism, Mice, Microscopy, Fluorescence, Phosphorylation, radiation effects, Protein Processing, Post-Translational, RAW 264.7 Cells, Signal Transduction
Référence
Cell Death Differ.. 2017 Jun;: