Respiratory sensitizer hexamethylene diisocyanate inhibits SOD 1 and induces ERK-dependent detoxifying and maturation pathways in dendritic-like cells |
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| Affiliation: | 1. Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal;2. Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal;3. Department of Chemistry, Mass Spectrometry Center, QOPNA, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;1. FMUC-Faculty of Medicine, University of Coimbra, Portugal;2. Pneumology Unit A, Centro Hospitalar e Universitário de Coimbra, Portugal;3. CNC - Centre for Neuroscience and Cell Biology, University of Coimbra, Portugal;4. Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Portugal;1. Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas and Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain;2. Research Group Neuroplasticity, Leibniz-Institute for Neurobiology, Magdeburg 39118, Germany;3. Cell Biology, Utrecht University, Utrecht 3584, the Netherlands;4. School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK;5. Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, Department of Health and Human Services, National Institutes of Health, Baltimore, MD 21224, USA;1. Oak Ridge Institute for Science Education Research Participation Program, Midcontinent Ecology Division, Duluth, MN, USA;2. Badger Technical Services, Midcontinent Ecology Division, Duluth, MN, USA;3. US Environmental Protection Agency, Midcontinent Ecology Division, Duluth, MN, USA;4. University of St. Thomas, Department of Biology, St. Paul, MN, USA;5. Harvard University, Organismic and Evolutionary Biology, Cambridge, MA, USA;6. University of Minnesota-Crookston, Department of Biology, Crookston, MN, USA |
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| Abstract: | Respiratory allergy to low-molecular-weight chemicals is a current concern in the context of occupational health, and a certified method to identify respiratory allergens is still under investigation. The aim of this work was to unveil some of the poorly understood initial molecular events and toxicity pathways underlying respiratory sensitization, which might be crucial to disclosing the key building blocks of new testing strategies and may contribute to the development of a valid in vitro method for the identification of respiratory allergens. Immortalized human dendritic cell (DC)-like THP-1 cells were exposed to the respiratory allergen hexamethylene diisocyanate (HDI) for 6 h, and the activation of several signaling pathways was analyzed. Mitochondrial membrane potential (MMP) alterations, superoxide anion (O2−) production, and gene expression modulation in HDI-treated cells were also evaluated. According to our results, HDI induces O2− increase (P < 0.001) through enzymatic inhibition of cytoplasmic superoxide dismutase 1 (P < 0.05), which might reduce MMP, further leading to mitochondrial O2− production. Increased O2− levels promote ERK phosphorylation (approx sixfold compared to control; P < 0.001) and downstream transcriptional increase of several genes: HMOX1 (P < 0.05), involved in the protection of chemical reactive species; MDR1 (P < 0.01), responsible for the efflux of xenobiotics in the cell; and CD83 (P < 0.05), a DC maturation marker. These results raise new perspectives on the action of respiratory allergens in DCs and point out key molecular events that are crucial for the development of the so-called adverse outcome pathways, particularly regarding O2− increase through enzymatic inhibition, and important for ERK activation. Furthermore, our results highlight the role of ERK signaling, but not p38 MAPK, in the activation of vital mechanisms in cells exposed to a respiratory allergen, such as cell detoxification, migration, and maturation. |
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| Keywords: | Respiratory allergy Mitochondria ROS SOD ERK MDR1 THP-1 dendritic cells Free radicals |
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