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

Overview

Journal Sci Rep

Specialty Science

Date 2018 Oct 28

PMID 30367171

Citations 10

Authors

Peter Jarver

Aleksandra Dondalska

Candice Poux

AnnSofi Sandberg

Joseph Bergenstrahle

Annette E Skold

Nathalie Dereuddre-Bosquet

Frederic Martinon

Sandra Palsson

Eman Zaghloul

David Brodin

Birgitta Sander

Kim A Lennox

Mark A Behlke

Samir El-Andaloussi

Janne Lehtio

Joakim Lundeberg

Roger Legrand

Anna-Lena Spetz

Affiliations

Soon will be listed here.

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.

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