Particulate matter stimulates the NADPH oxidase system via AhR-mediated epigenetic modifications

• Published in: Environmental pollution (1987) Vol. 347; p. 123675
• Main Authors: Kang, Kyoung Ah, Piao, Mei Jing, Fernando, Pincha Devage Sameera Madushan, Herath, Herath Mudiyanselage Udari Lakmini, Yi, Joo Mi, Choi, Yung Hyun, Hyun, Young-Min, Zhang, Kelun, Park, Chang Ook, Hyun, Jin Won
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.04.2024
• Subjects: Ca2+ release; Epigenetic modification; NADPH oxidases; Particulate matter 2.5; Reactive oxygen species; Reactive oxygen species; NADPH oxidases; Particulate matter 2.5; Epigenetic modification; Ca2+ release; Ca(2+) release
• ISSN: 0269-7491; 1873-6424
• DOI: 10.1016/j.envpol.2024.123675

Stimulation of human keratinocytes with particulate matter 2.5 (PM2.5) elicits complex signaling events, including a rise in the generation of reactive oxygen species (ROS). However, the mechanisms underlying PM2.5-induced ROS production remain unknown. Here, we show that PM2.5-induced ROS production in human keratinocytes is mediated via the NADPH oxidase (NOXs) system and the Ca2+ signaling pathway. PM2.5 treatment increased the expression of NOX1, NOX4, and a calcium-sensitive NOX, dual oxidase 1 (DUOX1), in human epidermal keratinocyte cell line. PM2.5 bound to aryl hydrocarbon receptor (AhR), and this complex bound to promoter regions of NOX1 and DUOX1, suggesting that AhR acted as a transcription factor of NOX1 and DUOX1. PM2.5 increased the transcription of DUOX1 via epigenetic modification. Moreover, a link between DNA demethylase and histone methyltransferase with the promoter regions of DUOX1 led to an elevation in the expression of DUOX1 mRNA. Interestingly, PM2.5 increased NOX4 expression and promoted the interaction of NOX4 and Ca2+ channels within the cytoplasmic membrane or endoplasmic reticulum, leading to Ca2+ release. The increase in intracellular Ca2+ concentration activated DUOX1, responsible for ROS production. Our findings provide evidence for a PM2.5-mediated ROS-generating system network, in which increased NOX1, NOX4, and DUOX1 expression serves as a ROS signal through AhR and Ca2+ activation. [Display omitted] •PM2.5 mediates AhR-DUOX1 expression by epigenetically modifying DNA and histones.•PM2.5 stimulates interaction of NOX4 and Ca2+ channels and leads to release of Ca2+.•Increased levels serve as an oxidative stress induced by PM2.5.