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

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Endosomal Toll-like receptors (TLRs) are crucial for pathogen recognition.
• Tight regulation of TLR signaling is necessary to prevent excessive inflammation.
• Mechanisms controlling TLR regulatory pathways remain largely unknown.

Purpose of the Study:

• To investigate the regulatory mechanisms of endosomal TLR signaling.
• To identify factors that control immune responses mediated by TLRs.
• To elucidate the role of extracellular nucleic acids in immune regulation.

Main Methods:

• Investigated the effect of single-stranded oligonucleotides (ssON) on endocytic pathways.
• Assessed ssON concentration and length dependence for endocytic inhibition.
• Analyzed modulation of TLR3/4/7 signaling downstream of affected endosomes.
• Evaluated ssON effects on dsRNA-mediated inflammation in non-human primates.

Main Results:

• Single-stranded oligonucleotides (ssON), including ssDNA and ssRNA, inhibit endocytic pathways.
• This inhibition is concentration-dependent and requires a minimum ssON length.
• ssON interfere with signaling downstream of TLRs within affected endosomes.
• ssON injection reduces dsRNA-induced inflammatory responses in primate skin.

Conclusions:

• Extracellular ssON play a regulatory role in the endocytic uptake of TLR ligands.
• ssON-mediated interference of endocytosis (SOMIE) temporarily dampens TLR3/4/7 signaling.
• SOMIE provides a mechanism to avert excessive immune responses, preventing harmful inflammation.