Järver P, Dondalska A, Poux C, Sandberg A, Bergenstråhle J, Sköld AE, Dereuddre-Bosquet N, Martinon F, Pålsson S, Zaghloul E, Brodin D, Sander B, Lennox KA, Behlke MA, El-Andaloussi S, Lehtiö J, Lundeberg J, LeGrand R, Spetz AL
Sci Rep 8 (1) 15841 [2018-10-26; online 2018-10-26]
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.