Toll like receptors (TLRs) are transmembrane proteins expressed by cells of innate immune system, which recognizes invading microorganisms and activate signaling pathways that launch immune and inflammatory responses to destroy/degrade invaders. They are pattern recognition receptors (PRRs).
These are a family of type I transmembrane pattern recognition receptors (PRRs) that sense invading pathogens or endogenous damage signals and initiate the innate and adaptive immune response.
Generally signals transduced through TLRs results in transcriptional activation and synthesis as well as secretion of cytokines which promote inflammatory responses that bring macrophages and neutrophils to the site of inflammation.
These were first identified in drosophila. 13 TLRs that function as PRRs have been identified in mice and human. TLRs 1-10 are conserved between mice and humans, although TLR10 is not functional in mice, while TLRs 11-13 are expressed in mice but not in humans. In mammals TLR family includes 11 proteins (i.e. TLR 1-11).
Structure: Mammalian TLRs consists of an extracellular portion consisting of leucine rich repeats (LRRs), a transmembrane region and a cytoplasmic tail called Toll interleukin-1 receptor (TIR) homology domain. Multiple leucine rich repeats make up the horseshoe-shaped extracellular ligand-binding domain of the TLR polypeptide chain.
TLRs and Ligands: Different TLRs serve as receptors for diverse ligands including bacterial cell wall components, viral double standard RNA and small molecule anti-viral or immune modulatory compounds.
|S.N.||Toll Like Receptors||Ligands (Pathogen associated molecular pattern i.e. PAMPs)|
|1.||TLR (1,2,6)||Gram positive bacteria (Lipoproteins, Lipo arabino-mannan, Lipopolysaccharides, Peptidoglycan, Zymosan of yeast).|
|2.||TLR-3||Virus (Double stranded RNA).|
|3.||TLR-4||Gram negative bacteria (Lipopolysaccharide, Lipid-A).|
|4.||TLR-5||Flagellated bacteria (Flagellin), Flagella|
|5.||TLR (7,8)||Virus (Single stranded RNA).|
|6.||TLR-9||Bacterial DNA [CpG DNA- Unmethylated Cytosine leads to Guanine].|
In addition to microbial ligands, TLRs also recognize Damage-associated molecular pattern (DAMPs), endogenous (self) components released by dead/ dying cells or damaged tissues. Among the DAMPS recognized by plasma membrane TLRs are heat shock and chromatin proteins, fragments of extracellular matrix components (such as fibronectin and hyaluronin), and oxidized low density lipoprotein and amyloid-β.
Activation of TLRs: Activation occurs after binding of cognate ligand to the extracellular leucine rich lipid portion. In human receptors [TLR- 1, 2, 4, 5 & 6] are outer membrane associated and respond primarily to bacterial surface associate Pathogen associated molecular pattern (PAMPs). The second group [i.e. TLR- 3, 7, 8 & 9] are found on surface of endosomes where they respond primarily to nucleic acid based PAMPs especially from virus and some few bacteria.
On binding with their cognates, these receptors activates two major signaling pathways:
- The core pathway utilized by most TLRs leading to activation of transcriptional factor, Nuclear factor-KB (NF-KB) and mitogen activated protein kinases P38 and JNK (c-Jun-N- terminal kinases).
- Other pathway involves TLR-3 and TLR-4 which leads to activation of both Nuclear factor-KB and another transcriptional factor Interferon regulation factor-3 (IRF-3) allowing for an additional set of genes to be induced including anti-viral genes such as Interferon-β (IFN- β) & others.
Bacterial cell wall endotoxins bind to innate immune system pathogen receptors, such as Toll-like receptors on dendritic cells and macrophages, causing them to produce Interleukin – 1 (IL-1) and as Interferon-α (TNF-α) at levels that lead to pathological capillary permeability & loss of blood pressure which leads to septic shock.
Characterization of the Toll protein reveals that its cytoplasmic signaling domain is homologous to vertebrate receptor for the cytokine IL-1 (IL-1R).
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