Endosomal nucleic acids

Endosomal nucleic acids, encompassing various forms of RNA and DNA, function as critical ligands for the innate immune system's pattern recognition receptors (PRRs) located within the endolysosomal pathway. These structures, including single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), and unmethylated CpG DNA, are specifically recognized by Toll-like receptors (TLR3, TLR7, TLR8, and TLR9) (Kuznik et al., 2011). Upon recognition, these receptors trigger signaling cascades that activate transcription factors like NF-κB and Interferon Regulatory Factors (IRFs), leading to the robust production of Type I interferons and pro-inflammatory cytokines (Fillatreau et al., 2021). While this mechanism is essential for the detection and clearance of viral and bacterial pathogens, the aberrant sensing of endogenous (self) nucleic acids is a central driver in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjogren's syndrome (Schrezenmeier & Dörner, 2020). Therapeutic targeting of this system involves several strategies, including the use of antimalarial drugs like hydroxychloroquine that inhibit endosomal acidification to prevent TLR activation, as well as the development of specific small-molecule and oligonucleotide-based antagonists that directly block receptor-ligand interactions (Sartorius et al., 2023). These interventions aim to dampen the chronic inflammatory state associated with autoimmune disorders while maintaining sufficient immune competence. Additionally, the sequestration of these nucleic acids or the modulation of their transport into endosomes represents an emerging area of pharmacological research. Monitoring the efficacy of such treatments often involves measuring the interferon signature, a collection of genes upregulated in response to the signaling initiated by these endosomal structures.

Other names

RNA and nucleic acid structures in endolysosomal compartmentsEndolysosomal nucleic acidsEndosomal TLR ligandsEndosomal RNAEndosomal DNA

Inhibition of endosomal acidification, direct antagonism of Toll-like receptors (TLR3, 7, 8, 9), and sequestration of nucleic acid ligands.