Enhanced Cellular Polysulfides Negatively Regulate TLR4 Signaling and Mitigate Lethal Endotoxin Shock

Cell Chem Biol. 2019 May 16;26(5):686-698.e4. doi: 10.1016/j.chembiol.2019.02.003. Epub 2019 Mar 7.


Cysteine persulfide and cysteine polysulfides are cysteine derivatives having sulfane sulfur atoms bound to cysteine thiol. Accumulating evidence has suggested that cysteine persulfides/polysulfides are abundant in prokaryotes and eukaryotes and play important roles in diverse biological processes such as antioxidant host defense and redox-dependent signal transduction. Here, we show that enhancement of cellular polysulfides by using polysulfide donors developed in this study resulted in marked inhibition of lipopolysaccharide (LPS)-initiated macrophage activation. Polysulfide donor treatment strongly suppressed LPS-induced pro-inflammatory responses in macrophages by inhibiting Toll-like receptor 4 (TLR4) signaling. Other TLR signaling stimulants-including zymosan A-TLR2 and poly(I:C)-TLR3-were also significantly suppressed by polysulfur donor treatment. Administration of polysulfide donors protected mice from lethal endotoxin shock. These data indicate that cellular polysulfides negatively regulate TLR4-mediated pro-inflammatory signaling and hence constitute a potential target for inflammatory disorders.

Keywords: cysteine persulfide; endotoxin shock; inflammation; innate immunity; metabolomics; polysulfide; signal transduction; sulfane sulfur; sulfur donor; toll-like receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glutathione / chemistry
  • Immunity, Innate / drug effects
  • Interferon-beta / metabolism
  • Lipopolysaccharides / toxicity
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nitrites / metabolism
  • Phosphorylation / drug effects
  • RAW 264.7 Cells
  • Signal Transduction / drug effects*
  • Sulfides / chemical synthesis
  • Sulfides / pharmacology*
  • Toll-Like Receptor 4 / chemistry
  • Toll-Like Receptor 4 / metabolism*
  • Tumor Necrosis Factor-alpha / blood


  • Lipopolysaccharides
  • Nitrites
  • Sulfides
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Interferon-beta
  • polysulfide
  • Extracellular Signal-Regulated MAP Kinases
  • Glutathione