A Biological Perspective of TLR8 Signaling in Host Defense and Inflammation

Abstract Toll-like receptors (TLRs) play important roles in immune responses against pathogens and tumors. Recently, TLR8 has gained attention because of its association with multiple inflammatory diseases, infections and anti-tumor responses. TLR8 senses the degradation products of single-stranded RNA from microbes and self-released RNA to induce type I interferons (IFN-Is), inflammatory gene expression and nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. So far, the understanding of TLR8 function in vivo is still limited, partially because of lacking a reliable rodent animal model. Murine Tlr8 cannot sense the ligands of human TLR8. In mammals, TLR8 distinguishes live bacteria from dead bacteria to regulate the magnitude of immune responses. Recently, TLR8 has been reported to recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA to induce inflammatory responses, suggesting that TLR8 participates in coronavirus disease 2019 (COVID-19). In this review, we discuss the mechanism of ligand recognition by TLR8, TLR8-mediated signaling pathways and signaling crosstalk between TLR8 and other molecules, and untangle the contribution of TLR8 to inflammatory diseases, infectious diseases, anti-tumor immunity and vaccination.