TLR Signaling Pathway

Innate immune receptors, also known as pattern recognition receptors (PRRs), have been identified in the serum, on the cell surface, in endosomes, and in the cytoplasm. Toll-like receptors (TLRs) is one of the particularly important groups of PRRs. TLR paralogs are located on cell surfaces or within endosomes and participate in the first line of defense against invading pathogens and play a crucial role in inflammation, immune cell regulation, survival, and proliferation.

TLR Family and Subfamilies

The TLR family has 10 members (TLR1–TLR10) in humans and 12 (TLR1–TLR9, TLR11–TLR13) in the mouse. In humans, 10 TLRs respond to a variety of pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (TLR4), lipopeptides (TLR2 associated with TLR1 or TLR6), bacterial flagellin (TLR5), viral dsRNA (TLR3), viral or bacterial ssRNA (TLRs 7 and 8), and CpG-rich unmethylated DNA (TLR9), among others. TLRs can be classified into two subfamilies in terms of their localization, cell surface TLRs and intracellular TLRs. All TLRs are listed in Table 1. Cell surface TLRs can recognize microbial membrane components, such as lipids, lipoproteins, and proteins. Intracellular TLRs are localized in the endosome and can recognize nucleic acids derived from bacteria and viruses, and also recognize self-nucleic acids in disease conditions such as autoimmunity.

Table.1 Summary of Toll-like receptors (TLRs)

The Structure of TLRs

TLRs are type I integral membrane receptors, each with an N-terminal ligand recognition domain, a single transmembrane helix, and a C-terminal cytoplasmic signaling domain. Furthermore, each TLR is composed of an ectodomain with leucine-rich repeats (LRRs) that are short motifs that fold into a characteristic solenoid structure and mediate PAMPs recognition, a transmembrane domain, and a cytoplasmic Toll/IL-1 receptor (TIR) domain that initiates downstream signaling.

TLR Signaling Pathway

The activation of the TLR signaling pathway starts from the cytoplasmic TIR domain that associates with a TIR domain-containing adaptor, MyD88. Upon stimulation with ligands, MyD88 recruits IL-1 receptor-associated kinase-4 (IRAK-4) to TLRs through the interaction of the death domains of both molecules. IRAK-1 is activated via phosphorylation and associates with TRAF6, leading to activate the IKK complex and leading to activation of MAP kinases, including JNK, p38, MAPK, and NF-κB. TOLLIP and IRAK-M interact with IRAK-1 and negatively regulate the TLR-mediated signaling pathways. In addition, there are other modes of regulation for these pathways include TRIF-dependent induction of TRAF6 signaling by RIP1 and negative regulation of TIRAP-mediated downstream signaling by ST2L, TRIAD3A, and SOCS1. Moreover, activation of MyD88-independent pathways occurs via TRIF and TRAF3, resulting in recruitment of IKKε/TBK1, phosphorylation of IRF3, and expression of interferon-β. TIR domain containing adaptors such as TIRAP, TRIF, and TRAM regulates TLR-mediated signaling pathways by providing specificity for individual TLR signaling cascades. TRAF3 plays a critical role in the regulation of both MyD88-dependent and TRIF-dependent signaling via TRAF3 degradation, which activates MyD88-dependent signaling and suppresses TRIF-dependent signaling (and vice versa).

Related Pathways

MAPK Signaling Pathway

For research use only. Not intended for any clinical use.