Nucleic acid-sensing TLRs: trafficking and regulation

•Nucleic acid-sensing TLRs are regulated at multiple levels to maintain immunological tolerance to host-derived ligands.•The recently solved crystal structures of TLR7, TLR8, and TLR9 provide evidence for the need of proteolytic processing and the mode of ligand binding.•TLR7 and TLR8 are dual receptors for single nucleosides and short ssRNA oligoribonucleotides.•The need for ligand processing to generate stimulatory nucleic acid fragments emerges as a new principle for TLR activation.

Toll-like receptors (TLRs) play an important role in innate immune responses against pathogenic microorganisms or tissue damage. Nucleic acid (NA)-sensing TLRs localize in intracellular vesicular compartments and recognize foreign-derived and host-derived nucleic acid ligands. Inappropriate activation of NA-sensing TLRs can cause pathogenic inflammation and autoimmunity. Multiple regulatory mechanisms exist to limit recognition of self-NAs. This review summarizes recent progress that has been made in understanding how NA-sensing TLRs are regulated via trafficking, proteolytic cleavage, as well as ligand processing and recognition.