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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

Peter Järver, Aleksandra Dondalska, Candice Poux, AnnSofi Sandberg, Joseph Bergenstråhle, Annette E. Sköld, Nathalie Dereuddre-Bosquet, Fréderic Martinon, Sandra Pålsson, Eman Zaghloul, David Brodin, Birgitta Sander, Kim A. Lennox, Mark A. Behlke, Samir EL-Andaloussi, Janne Lehtiö, Joakim Lundeberg, Roger LeGrand, Anna-Lena Spetz

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. More... »

PAGES

15841

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-018-33960-4

DOI

http://dx.doi.org/10.1038/s41598-018-33960-4

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1107771917

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30367171


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