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.

中文翻译：

---

单链核酸通过干扰网格蛋白介导的内吞作用来调节TLR3 / 4/7活化。

内体Toll样受体（TLR）识别核酸对于抵抗病原体至关重要，但需要严格控制以限制炎症反应。监管这种严格监管的机制尚不清楚。我们发现，单链寡核苷酸（ssON）抑制了目的地为TLR3 / 4/7信号内体的货物所使用的内吞途径。ssDNA和ssRNA均具有内吞抑制作用，它是浓度依赖性的，并且需要一定的ssON长度。ssON介导的抑制作用可调节位于受影响的内体途径内的TLR下游的信号传导。我们进一步表明，注射ssON可以抑制dsRNA介导的非人类灵长类动物皮肤中的炎症反应。这些研究揭示了胞外ssON在TLR配体的内吞摄取中的调节作用，并提供了其免疫调节的机制解释。已确定的ssON介导的内吞作用干扰（SOMIE）是一种调节性过程，可暂时抑制TLR3 / 4/7信号传导，从而避免过度的免疫反应。