Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Järver, Peter; Dondalska, Aleksandra; Poux, Candice; Sandberg, AnnSofi; Bergenstråhle, Joseph; Sköld, Annette; Dereuddre-Bosquet, Nathalie; Martinon, Fréderic; Pålsson, Sandra; Zaghloul, Eman; Brodin, David; Sander, Birgitta; Lennox, Kim; Behlke, Mark; EL-Andaloussi, Samir; Lehtiö, Janne; Lundeberg, Joakim; LeGrand, Roger; Spetz, Anna-Lena
• Is Part Of: Scientific reports. Volume 8:Issue 1(2018)
• Page Start: 1
• Page End: 17
• Publication Date: 2018-12
• Subjects: Natural history -- Research -- Periodicals; Biology -- Research -- Periodicals; Physical sciences -- Research -- Periodicals; Earth sciences -- Research -- Periodicals; Environmental sciences -- Research -- Periodicals; 502.85
• DOI: 10.1038/s41598-018-33960-4
• Languages: English
• ISSNs: 2045-2322

Abstract

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.