Toll-like receptors 7 and 8 as therapeutic targets for human diseases.

Toll-like receptor 7 (TLR7) and TLR8 respond to pathogen-derived single-stranded RNA (ssRNA), orchestrating innate immune defense responses upon infections. However, aberrant recognition of endogenous ssRNAs by these sensors can cause various pathologies, including systemic lupus erythematosus (SLE), familial histiocytosis, immunodeficiency, and bone marrow failure. Recent insights into genetic variations in TLR7/8 and functionally associated genes have elucidated the mechanisms that prevent excessive TLR7/8 activation. Specifically, TLR7/8 responses are negatively regulated by several mechanisms, including the TLR-specific chaperone UNC93B1, lysosomal NADPH oxidase NOX2, the lysosomal nuclease PLD4, and the lysosomal nucleoside transporter SLC29A3. Given the link between dysregulated TLR7/8 activation and diseases development, therapeutic agents targeting these receptors are currently under clinical trials to evaluate their efficacy in treating SLE.