Endosomal recognition of single stranded (ss) RNA occurs by means of toll-like receptor 7 (TLR7) and TLR8 which are expressed in macrophages, dendritic cells (DCs), and B cells. Upon engagement of ssRNAs in endosomes, TLR7 and TLR8 initiate the MyD88‑dependent pathway, leading to production of type I and type III IFNs and proinflammatory mediators via activation of IRF7 and NF‑kappa-B, respectively (reviewed in Lester SN & Li K 2014). TLR7 and TLR8 detect uridine (U)-rich ssRNA sequences from the viral genomes including lentivirus (human immunodeficiency virus-1, HIV-1) and betacoronavirus (severe acute respiratory syndrome-associated coronavirus type 1, SARS-CoV-1 and SARS-CoV-2) (Heil F et al., 2004; Li Y et al., 2013; Campbell GR et al., 2021). TLR7 and TLR8 may also respond to endogenous immune complexes containing self-ssRNA (Vollmer J et al., 2005; Savarese E et al., 2006; Hung T et al., 2015; Lee J et al., 2022; reviewed by Mu X et al., 2016). In human and mouse cells, TLR7 was shown to bind small endogenous molecules such as guanosine (G) and G-derivatives, 2',3'-cyclophosphate guanosine monophosphate (2',3'-cGMP), deoxyguanosine (dG) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) (Zhang Z et al., 2016, 2018; Shibata T et al., 2016; Davenne T et al., 2020). 8-OHdG, an oxidized nucleoside of DNA, is considered as a biomarker of oxidative DNA damage.
Structural analyses have revealed that both TLR7 and TLR8 possess two binding sites (Tanji H et al., 2015; Zhang Z et al., 2016). Binding site 1 is highly conserved between TLR7 and TLR8 and binds nucleosides (G for TLR7 and U for TLR8) or nucleoside analogs (Zhang Z et al., 2016). Binding site 2 of TLR7 and TLR8 is less conserved and binds ssRNA with U(U) and U(G) motifs. TLR7 acts as a dual receptor for G and U‑containing ssRNAs (Zhang Z et al., 2016). Binding of ssRNA to the site 2 of TLR7 is thought to enhance the interaction of TLR7 with G or G derivatives at the first site leading to subsequent receptor dimerization (Zhang Z et al., 2016, 2018; Shibata T et al., 2016). Notably, dG induces TLR7-mediated activation of inflammatory cytokines in the absence of ssRNA (Davenne T et al., 2020).
Dysregulation of TLR7-mediated response to self-ligands may lead to an aberrant B cell signaling which is associated with the pathogenesis of autoantibody driven autoimmune diseases such as systemic lupus erythematosus (SLE) (Green NM et al., 2012; Sakata K et al., 2018). Systemic lupus erythematosus (SLE)-associated TLR7 Y264H mutation within the small endogenous molecule binding sites is a X chromosome‑linked dominant gain‑of‑function variant, that selectively increases sensing of G and 2',3'‑cGMP causing enhanced TLR7 activation (Brown GJ et al., 2022).
Hydroxychloroquine (HCQ) binds and antagonizes TLR7 (Lamphier M et al., 2014), and thus inhibits interferon alpha production. HCQ is used clinically to treat SLE and other autoimmune disorders (Costedoat‑Chalumeau N et al., 2014).
This Reactome event shows TLR7 binding to endogenous G or its derivatives dG, 2',3'-cGMP and 8-OHdG.
