Toll-like receptors (TLRs)

Sentinels of immune system essential for stimulation of adaptive immunity against invading microorganisms.

Transmembrane proteins on surface of immune cells that detect conserved microbe associated molecular patterns form organisms.


Toll-like receptors (TLRs) are a protein class that play a key role in the innate immune system. 



They are receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. 



If microbes  breach  physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. 



The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, and TLR10



Toll-like receptors (TLRs) have the ability of the immune system to recognize pathogens and are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity T cells, and B cells, and non immune cells, such as epithelial and endothelial cells, and fibroblasts.



The binding of ligands by adjuvant used in vaccinations or in the form of invasive organisms during times of natural infection, to the TLR marks ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.



When activated TLRs recruit adaptor proteins within the cytosol of the immune cell in order to propagate the antigen-induced signal transduction pathway. 



These recruited proteins activate downstream proteins, including protein kinases that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events, including cytokine production, proliferation, and survival,  and greater adaptive immunity.



With a bacterial ligand, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells. 



In the case of a viral pathogen the infected cell may shut off its protein synthesis and may undergo apoptosis.



Toll-like receptors have a link between innate and adaptive immunity through their presence in dendritic cells.



Flagellin, is a TLR5 ligand that induces cytokine secretion on interacting with TLR5 on human T cells.



TLRs are a type of pattern recognition receptor that recognize molecules that are broadly shared by pathogens but distinguishable from host molecules.



TLRs together with the Interleukin-1 receptors form a receptor superfamily, known as the “interleukin-1 receptor / toll-like receptor superfamily”.



Three subgroups of T-Interleukin receptor domains exist. 



Proteins with subgroup 1 TIR domains are receptors for interleukins that are produced by macrophages, monocytes, and dendritic cells.



All subgroups have extracellular Immunoglobulin (Ig) domains. 



TIR domains are classical TLRs, and bind directly or indirectly to molecules of microbial origin. 



TLR are detected on glia, neurons and on neural progenitor cells.



Thirteen TLRs have been identified.



The Toll pathway is activated by multiple  stimuli, such as Gram positive bacteria, fungi and virulence factors.



Stmulation of TLR3 causes great changes in chromatin remodeling and nuclear reprogramming, and activation of inflammatory pathways is required for these changes, induction of pluripotency genes and generation of human induced pluripotent stem cells colonies.



Toll-like receptors bind and are activated by different ligands.



These ligands are located on different types of organisms or structures. 



Toll-like receptors have  varying adapters to respond to activation and are located sometimes at the cell surface and sometimes to internal cell compartments. 



These adaptors are expressed by different types of leucocytes or other cell types: 






a subset of dendritic cells



B lymphocytes



Myeloid dendritic cells



Mast cells



Toll-like receptors (TLRs) recognize molecules associated with pathogens that  are threats and do not mistake 


 self molecules that are normally expressed under physiological conditions.



Pathogen features include: 


bacterial cell-surface lipopolysaccharides (LPS), lipoproteins, proteins such as flagellin,  from bacterial flagella, double-stranded RNA of viruses, bacterial and viral DNA.



Endogenous activators of toll-like receptors might participate in autoimmune diseases. 



TLRs. may bind to host molecules including fibrinogen, heat shock proteins, extracellular matrix components and self DNA.



In the presence of inflammatory and autoimmune conditions it can form complexes with endogenous proteins, become resistant to these nucleases.



Such complexes can  gain access to endosomal TLRs.



Endosomal TLRs recognize nucleic acid derived from viruses as well as endogenous nucleic acids in context of pathogenic events. 



Activation of these TLR receptors leads to production of inflammatory cytokines as well as type I interferons to help fight viral infection.



TLRs recruit adapter molecules within the cells in order to propagate a signal. 



Four adapter molecules are known to be involved in signaling: MyD88, TIRAP,TRIF, and TRAM (TRIF-related adaptor molecule).



TLR signaling induces  or suppresses genes that orchestrate the inflammatory response. 



Thousands of genes are activated by TLR signaling



TLR4 is the only TLR that uses all four adaptors. 



Imiquimod is a TLR7 agonist.

Interact with a number of adapter proteins activating transcription factors, leading to the production of inflammatory cytokines and activation of adaptive immunity.

Platelets and megakaryocytes express such receptors.

Expressed by eosinophils.

Viral nucleic acids, including double stranded RNA, single stranded RNA and double stranded DNA are recognized by TLR-3,-7 and -9, respectively and produces type I interferons and initiates antiviral response.

Polymorphisms in TLR genes associated with increased susceptibility of infections.

TLR4 haplotypes in donors associated with increased risks of invasive aspergillosis among recipients of allogeneic hematopoietic cell transplants.

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