Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis

Sci Rep. 2018 Oct 26;8(1):15841. doi: 10.1038/s41598-018-33960-4.

Abstract

Recognition of nucleic acids by endosomal Toll-like receptors (TLR) is essential to combat pathogens, but requires strict control to limit inflammatory responses. The mechanisms governing this tight regulation are unclear. We found that single-stranded oligonucleotides (ssON) inhibit endocytic pathways used by cargo destined for TLR3/4/7 signaling endosomes. Both ssDNA and ssRNA conferred the endocytic inhibition, it was concentration dependent, and required a certain ssON length. The ssON-mediated inhibition modulated signaling downstream of TLRs that localized within the affected endosomal pathway. We further show that injection of ssON dampens dsRNA-mediated inflammatory responses in the skin of non-human primates. These studies reveal a regulatory role for extracellular ssON in the endocytic uptake of TLR ligands and provide a mechanistic explanation of their immunomodulation. The identified ssON-mediated interference of endocytosis (SOMIE) is a regulatory process that temporarily dampens TLR3/4/7 signaling, thereby averting excessive immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chemokines / metabolism
  • Clathrin / metabolism*
  • Cytokines / metabolism
  • DNA, Single-Stranded / pharmacology
  • Endocytosis / drug effects*
  • Endosomes / metabolism
  • Humans
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Macaca fascicularis
  • Oligonucleotides / pharmacology*
  • Poly I-C / pharmacology
  • Signal Transduction / drug effects
  • Skin / metabolism
  • Skin / pathology
  • Toll-Like Receptor 3 / antagonists & inhibitors
  • Toll-Like Receptor 3 / metabolism*
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / metabolism*
  • Toll-Like Receptor 7 / antagonists & inhibitors
  • Toll-Like Receptor 7 / metabolism*

Substances

  • Chemokines
  • Clathrin
  • Cytokines
  • DNA, Single-Stranded
  • Oligonucleotides
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7
  • Poly I-C