Toll like receptor(TLR)

 

Toll-like receptors (TLRs)

 

Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) that initiate the innate immune response by sensing conserved molecular patterns for early immune recognition of a pathogen .TLRs are type I transmembrane proteins that contain three structural domains: a leucine-rich repeats (LRRs) motif, a transmembrane domain, and a cytoplasmic Toll/IL-1 receptor (TIR) domain. The LRRs motif is responsible for pathogen recognition, whereas the TIR domain interacts with signal transduction adaptors and initiates signaling. Toll-like receptors were first found in Drosophila melanogaster . 10 TLRs have been identified in human (TLR1–TLR10) and 13 in mouse (TLR1–TLR13).

 

Many of the molecules involved in innate immunity have the property of pattern recognition, the ability to recognize a given class of molecules. There are certain types of molecules that are unique to microbes and never found in multicellular organisms, the ability to immediately recognize and combat invaders displaying such molecules is a strong feature of innate immunity. Molecules with pattern recognition ability may be soluble, like lysozyme and the complement components described above, or they may be cell-associated receptors. Among the class of receptors designated the toll-like receptors (TLRs), TLR2 recognizes the lipopolysaccharide (LPS) found on Gram-negative bacteria.

Systemic exposure of mammals to relatively small quantities of purified LPS leads to an acute inflammatory response. The mechanism for this response is via a TLR on macrophages that recognizes LPS and elicits a variety of molecules in the inflammatory response upon exposure. When the TLR is exposed to the LPS upon local invasion by a Gram-negative bacterium, the response result in elimination of the bacteria. The toll-like receptors (TLRs) are important in recognizing many microbial patterns and mediate the recognition and generation of defensive responses to pathogens Typically, signals transduced through the TLRs cause transcriptional activation and the synthesis and secretion of cytokines, which promote inflammatory responses that bring macrophages and neutrophils to sites of inflammation.

Currently, TLR signaling pathways are classified into two distinct types, namely, the myeloid differentiation primary response protein 88 (MyD88)-dependent pathways and the TIR domain-containing adaptor-inducing IFNβ (TRIF)-dependent pathways.

 

 

 

Myeloid differentiation primary response protein 88 (MyD88)-dependent pathway

Ø The MyD88-dependent response is utilized by almost all the TLRs, with the exception of TLR3.

Ø Upon ligand recognition and TLR dimerization, MyD88 protein binds to the TIR domain of the corresponding TLR through homotypic/heterotypic interactions.

Ø Subsequently, IL-1 receptor-associated kinase 4 (IRAK4) is recruited and leading to the formation of a Myddosome complex, and autophosphorylation of IL-1 receptor-associated kinase 1 (IRAK1).

 

Ø Afterward, the protein tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is activated, which in turn activates the TAK1/TGF-β-activated kinase (TAB) complex through K-63-linked polyubiquitination of TAK1 and TRAF6.

Ø This is followed by IκB kinase (IKK)-mediated phosphorylation and degradation of I kappa B alpha (IκBα).

Ø Degradation of this inhibitor finally leads to nuclear translocation of the transcription factor NF-κB, which induces the transcription of genes encoding inflammatory cytokines.

 

 

TIR domain-containing adaptor-inducing IFNβ (TRIF)-dependent pathway.

Ø Generally, the TRIF-dependent pathway is considered to be specific for only few TLRs, such as TLR3 and TLR4 in mammals.

Ø Transcription factors, including NF-κB, activating protein-1 (AP-1), and interferon (IFN) regulatory factor (IRF) family members, can be activated by the TRIF-dependent pathway, collectively inducing the production of pro-inflammatory cytokines and/or type I IFN (IFN1).

Ø TLR3 is activated by recognizing double-stranded RNA (dsRNA), which is followed by the recruitment of TRIF.

Ø TRIF activates TANK-binding kinase 1 (TBK1) and receptor-interacting serine/threonine kinase 1 (RIPK1), respectively, which creates a signaling pathway.

Ø The TRIF/TBK1 signaling complex phosphorylates IRF3, allowing its translocation to the nucleus and the production of IFN1.

Ø Activation of RIPK1 causes a series of signal transduction events in the same manner as the MyD88-dependent pathway.

Ø TLR4 functions as an LPS receptor in mammals.

Ø After the recruitment of MyD88 and MyD88-adapter-like (MAL) adaptors, the TLR4-myeloid differentiation protein 2 (MD2)-LPS complex activates early-phase NF-κB and mitogen-activated protein kinase (MAPK).

Ø After the TLR4-MD2–LPS complex enters the cell via endocytosis, it interacts with the TRIF and TIR domain-containing adapter molecule 2 (TICAM2, also known as TRAM) adaptors.

Ø This TRIF-dependent pathway not only induces the production of IFN1 but also activates IRF7 and late-phase NF-κB.

Ø Ultimately, the TLR signaling leads to the induction or suppression of genes that fine-tune the inflammatory response.