4-Octyl Itaconate ameliorates diesel exhaust particle-induced oxidative stress in nasal epithelial cells

Hanna Steppuhn¹Katja Hohenberger¹Susanne Mittler¹Sonja Trump¹Manfred Rauh²Andreas B Wild³Nikolaos (Nikos) G Papadopoulos^4,5Susetta Finotto^1,6,7*

• ¹Molecular Pneumology, University Hospital Erlangen, Erlangen, Germany
• ²Universitatsklinikum Erlangen Kinder- und Jugendklinik, Erlangen, Germany
• ³Department of Immunomodulation, Universitatsklinikum Erlangen, Erlangen, Germany
• ⁴Center for Respiratory Medicine & Allergy, The University of Manchester School of Biological Sciences, Manchester, United Kingdom
• ⁵Department of Allergy, Ethniko kai Kapodistriako Panepistemio Athenon, Athens, Greece
• ⁶Bayerisches Zentrum fur Krebsforschung, Erlangen, Germany
• ⁷Comprehensive Cancer Center Erlangen, Erlangen, Germany

Background and objective Particulate matter such as diesel exhaust particles induce oxidative stress in cells and thereby have a negative impact on health. The aim of this study was to test whether the membrane permeable, anti-inflammatory metabolite 4-Octyl Itaconate can counteract the oxidative stress induced by diesel exhaust particles and to analyze the downstream regulated pathways both in human nasal epithelial cells and PBMCs. Methods Human nasal epithelial cells were cultured from nasal swabs and the response of the cells to diesel exhaust particles either alone or in combination with 4-Octyl Itaconate was investigated using RNA sequencing, qPCR and cytokine measurement. The presence of reactive oxygen species in the cells was analyzed using CellROX staining and flow cytometric DCFDA assay. Results Diesel exhaust particles caused an upregulation of CYP1A1 in nasal epithelial cells. The administration of 4-Octyl Itaconate reduced reactive oxygen species and increased the expression of antioxidant genes regulated by the transcription factor NRF2, which was also confirmed in PBMCs. IL-6 secretion from NEC was elevated by diesel exhaust particles and reduced when 4 Octyl Itaconate was administered. Conclusion 4-Octyl Itaconate can reduce the diesel exhaust particle-induced oxidative damage by activation of NRF2 regulated antioxidative pathways.