title: Oxidative stress-dependent activation of the eIF2α–ATF4 unfolded protein response branch by skin sensitizer 1-fluoro-2,4-dinitrobenzene modulates dendritic-like cell maturation and inflammatory status in a biphasic manner [corrected].
abstract: The pathogenesis of allergic contact dermatitis, the most common manifestation of immunotoxicity in humans, is intimately connected to hapten-induced maturation of dendritic cells (DC). The molecular mechanisms driving this maturational program are not completely known; however, initial danger signals such as the generation of reactive oxygen species (ROS) were shown to play a critical role. Recent evidence linking ROS production, endoplasmic reticulum (ER) stress, and the pathogenesis of several inflammatory diseases led us to analyze, in the present work, the ability of the skin sensitizer 1-fluoro-2,4-dinitrobenzene (DNFB) to evoke ER stress in DC-like THP-1 cells and the concomitant consequences to their immunobiology. We found that DNFB triggers a ROS-dependent activation of the PERK-eIFα-ATF4 unfolded protein response (UPR) branch conferring cytoprotection and modulating the maturation/proinflammatory cell status in a biphasic manner. Early DNFB induction of ATF4 positively modulates autophagy-related genes MAP1LC3B and ATG3 and stabilizes the transcription factor Nrf2, causing a strong induction of the HMOX1-detoxifying gene. Moreover, we observed that in a first phase, DNFB-induced ATF4 upregulates IL8 mRNA levels while blocking CD86, IL1B, IL12B, and CXL10 transcription. Later, following ATF4 decay, HMOX1 and IL8 transcription drastically decrease and CD86, IL1B, and Il12B are upregulated. Overall, our results evidence a connection between sensitizer-induced redox imbalance and the establishment of ER stress in DC-like cells and provide new insights into the role of UPR effectors such as ATF4 to the complex DC maturational program.
authors.affiliation: Department of Chemistry, Mass Spectrometry Centre, QOPNA, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Luís
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra 3004-517, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra 3004-517, Coimbra, Portugal.
authors.forename: João Demétrio
authors.initials: JD
authors.lastname: Martins
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra 3004-517, Coimbra, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Silva
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra 3004-517, Coimbra, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferreira
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra 3004-517, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra 3004-517, Coimbra, Portugal.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Cruz
authors.affiliation: Department of Chemistry, Mass Spectrometry Centre, QOPNA, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal; Centre for Neuroscience and Cell Biology, University of Coimbra 3004-517, Coimbra, Portugal. Electronic address: neves_bruno@sapo.pt.
authors.forename: Bruno Miguel
authors.initials: BM
authors.lastname: Neves
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D001343:Autophagy; D002460:Cell Line; D002470:Cell Survival; D004139:Dinitrofluorobenzene / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007801:Langerhans Cells / Q000187:drug effects / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism; D015533:Transcriptional Activation; D056811:Unfolded Protein Response
chemical_list: C497109:ATF4 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D051701:Activating Transcription Factor 4; D004139:Dinitrofluorobenzene
keywords: ATF4; Allergic contact dermatitis; Autophagy; Dendritic cell maturation; ER stress; ROS