Retinoic acid-inducible gene I-like receptor and endosomal Toll-like receptor (RLR and endosomal TLR)

Retinoic acid-inducible gene I-like receptor (RLR) and endosomal Toll-like receptor (TLR) are critical components of the innate immune system that function as pattern recognition receptors (PRRs) to detect non-self nucleic acids (NIH, 1.1.1). RLRs, including RIG-I (DDX58), MDA5 (IFIH1), and LGP2 (DHX58), are cytosolic RNA helicases that sense viral double-stranded RNA and 5'-triphosphorylated RNA (NIH, 1.3.4). Endosomal TLRs, specifically TLR3, TLR7, TLR8, and TLR9, monitor the endocytic pathway for foreign RNA and DNA (NIH, 1.1.2). Activation of these receptors triggers signaling cascades involving adapter proteins like MAVS, MyD88, and TRIF, ultimately leading to the production of type I interferons and pro-inflammatory cytokines (NIH, 1.2.1). These pathways are major therapeutic targets for the development of antiviral agents and cancer immunotherapies, where agonists like imiquimod and rintatolimod are used to stimulate a robust immune response (NIH, 1.3.2, 1.3.3). However, overactivation of these sensors is linked to the pathogenesis of autoimmune and autoinflammatory diseases, making them potential targets for inhibitory strategies as well (NIH, 1.1.2, 1.3.5). Therapeutic challenges include the risk of systemic inflammation and the need for precise delivery to avoid off-target effects (NIH, 1.3.5). Ongoing research focuses on optimizing the potency and safety of these agonists for use as vaccine adjuvants and in combination with other immunotherapies (NIH, 1.3.2).

Other names

RLRs and endosomal TLRsNucleic acid-sensing pattern recognition receptorsRNA and DNA sensorsCytosolic and endosomal PRRs

Agonism of these receptors triggers signaling pathways (via MAVS for RLRs and MyD88/TRIF for endosomal TLRs) that activate transcription factors IRF3, IRF7, and NF-kB, leading to the expression of type I interferons and pro-inflammatory cytokines (NIH, 1.2.1, 1.3.4).