Particulate matter induces inflammatory cytokine production via activation of NFκB by TLR5-NOX4-ROS signaling in human skin keratinocyte and mouse skin

Redox Biol. 2019 Feb;21:101080. doi: 10.1016/j.redox.2018.101080. Epub 2018 Dec 15.

Abstract

Particulate matter (PM) increases levels of pro-inflammatory cytokines, but its effects on the skin remain largely unknown. We investigated the signal transduction pathway and epigenetic regulatory mechanisms underlying cellular inflammation induced by PM with a diameter of ≤ 2.5 (PM2.5) in vitro and in vivo. PM2.5-treated skin keratinocytes produced various inflammatory cytokines, including IL-6. The binding of PM2.5 to TLR5 initiated intracellular signaling through MyD88, and led to the translocation of NFκB to the nucleus, where it bound the NFκB site within IL-6 promoter. Furthermore, PM2.5 induced a direct interaction between TLR5 and NOX4, and in turn induced the production of ROS and activated NFκB-IL-6 downstream, which was prevented by siRNA-mediated knockdown of NOX4 or antioxidant treatment. Furthermore, expression of TLR5, MyD88, NOX4, phospho-NFκB, and IL-6 was increased in skin tissue of PM2.5-treated flaky tail mice. PM2.5-induced increased transcription of IL-6 was regulated via DNA methylation and histone methylation by epigenetic modification; the binding of DNA demethylase and histone methyltransferase to the IL-6 promoter regions resulted in increased IL-6 mRNA expression. Our findings provide deep insight into the pathogenesis of PM2.5 exposure and can be used as a therapeutic strategy to treat inflammatory skin diseases caused by PM2.5 exposure.

Keywords: Epigenetic modification; Interleukin-6; Particulate matter; Reactive oxygen species; Toll like receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • Epigenesis, Genetic
  • Humans
  • Inflammation Mediators / metabolism*
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • Mice
  • Models, Biological
  • NADPH Oxidase 4 / metabolism*
  • NF-kappa B / metabolism*
  • Oxidative Stress
  • Particulate Matter / adverse effects*
  • Promoter Regions, Genetic
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Skin / metabolism*
  • Skin / pathology
  • Toll-Like Receptor 5 / metabolism*
  • Transcription, Genetic

Substances

  • Cytokines
  • Inflammation Mediators
  • NF-kappa B
  • Particulate Matter
  • Reactive Oxygen Species
  • Toll-Like Receptor 5
  • NADPH Oxidase 4