Toll-like receptors (TLRs) are critical pattern recognition receptors (PRRs) in the innate immune system, detecting pathogen-associated molecular patterns (PAMPs) to initiate immune responses.
Structure and Ligand Recognition
TLRs are transmembrane proteins with extracellular leucine-rich repeat (LRR) domains for ligand binding, a transmembrane region, and an intracellular Toll/IL-1 receptor (TIR) domain for signaling (Abbas et al., 2021). Each TLR recognizes specific PAMPs; for example, TLR4 binds lipopolysaccharide (LPS) from Gram-negative bacteria, while TLR3 detects viral double-stranded RNA. Ligand binding induces receptor dimerization, initiating signal transduction.
Signaling Pathways
TLR activation triggers intracellular signaling through adaptor proteins, primarily MyD88 and TRIF (Abbas et al., 2021). The MyD88-dependent pathway, used by most TLRs, activates NF-κB, leading to pro-inflammatory cytokine production (e.g., TNF-α, IL-6). TLR3 and, in some cases, TLR4 use the TRIF-dependent pathway to induce type I interferons, critical for antiviral immunity. These pathways amplify immune responses but require regulation to prevent excessive inflammation (Figure 1).
Figure 1: Structure, location, and specificities of mammalian Toll-like Receptors (Abbas et al., 2022)
References :
Abbas, A.K., Lichtman, A.H. and Pillai, S., 2021. Cellular and Molecular Immunology, 10e.