Signalling Mechanisms for Toll-like Receptors

Chu-Xiao Wang^*
*Correspondence: Chu-Xiao Wang, College of Life Sciences, Zhejiang University, Hangzhou, P.R. China, Email:

Description

Toll-like receptors (TLRs), which recognise pathogen-associated molecular patterns originating from diverse microorganisms, are essential components of the innate immune system. TLRs communicate by attracting particular adaptor molecules, which activates the transcription factors NF-B and IRFs, which control how innate immune responses develop. The specific mechanisms underpinning TLR signalling have been elucidated during the past ten years by a variety of methods involving genetic, biochemical, structural, cell biology, and bioinformatics studies. Divergent TLR signalling seems to be involved in several facets of the innate immune responses to certain infections. In this review, we discuss recent developments in our knowledge of how TLR signalling modulation affects host defence [1].

Pattern-recognition Receptors (PRRs), which are germline-encoded, are used by the innate immune system to identify microorganisms initially. Pathogen-associated molecular patterns (PAMPs), which are unique to each bacterium, and damage-associated molecular patterns, which are selfgenerated molecules formed from injured cells, are recognised by PRRs (DAMPs). By generating inflammatory cytokines, type I interferon (IFN), and other mediators, PRRs activate downstream signalling pathways that trigger the activation of innate immune responses. These pathways also prime and direct antigen-specific adaptive immune responses in addition to immediately initiating host defensive responses like inflammation. Both the removal of infectious microorganisms and the subsequent training of antigen-specific adaptive immune responses depend on these responses [2].

Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), Nod-like receptors (NLRs), AIM2-like receptors (ALRs), C-type lectin receptors (CLRs), and intracellular DNA sensors like cGAS are only a few of the different kinds of PRRs found in mammals. TLRs are the most well-known of these because they were the first to be discovered. The TLR family has 12 members (TLR1- TLR9, TLR11-TLR13) in mice and 10 members (TLR1-TLR10) in humans. TLRs can be found on the cell surface or in internal spaces like the ER, endosome, lysosome, or endolysosome. They can detect PAMPs including lipid, lipoprotein, protein, and nucleic acid that are unique or overlapping. Each TLR is made up of a transmembrane domain, a cytoplasmic Toll/IL-1 receptor (TIR) domain, and an ectodomain with leucine-rich repeats (LRRs) that facilitate PAMP recognition.

TLRs interact with their respective PAMPs or DAMPs as a homo- or heterodimer with a co-receptor or accessory molecule, and the ectodomain has a horseshoe-like form (4). The activation of NF-B, IRFs, or MAP kinases to control the expression of cytokines, chemokines, and type I IFNs that ultimately protect the host from microbial infection results from the recruitment of TIR domain-containing adaptor proteins like MyD88 and TRIF by TLRs upon recognition of PAMPs and DAMPs. Recent research has shown that correct cellular localization of TLRs is crucial for the control of signalling and that distinct innate immune responses are determined by cell type-specific signalling downstream of TLRs. Here, we review current research on TLR signalling pathways and how they affect host defence [3].

PAMP recognition

TLRs are expressed by both immune and non-immune cells, including fibroblast and epithelial cells, as well as innate immune cells like dendritic cells (DCs) and macrophages. TLRs are primarily divided into two subfamilies, cell surface TLRs and intracellular TLRs, based on where they are found. TLRs with endosomal localization include TLR3, TLR7, TLR8, TLR9, TLR11, TLR12, and TLR13, while cell surface TLRs include TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10.

Cell exterior TLRs primarily identify the lipids, lipoproteins, and proteins that make up microbial membranes. TLR4 can detect lipopolysaccharide from bacteria (LPS). A wide range of PAMPs, such as lipoproteins, peptidoglycans, lipotechoic acids, zymosan, mannan, and tGPI-mucin, are recognised by TLR2 in conjunction with TLR1 or TLR6. Bacterial flagellin is recognised by TLR5. Due to the inclusion of a stop codon, TLR10 is a pseudogene in mice; nonetheless, human TLR10 works with TLR2 to identify ligands from listeria. TLR10 can detect influenza a virus infection in addition.

In addition to recognising self-nucleic acids in circumstances like autoimmunity, intracellular TLRs also identify nucleic acids from bacteria and viruses. TLR3 can detect self-RNA produced by harmed cells, short interfering RNAs, and double-stranded RNA from viruses. Plasmacytoid DCs (pDCs) are the main cell types that express TLR7, which may detect single-stranded (ss) RNA from viruses. Additionally, it detects the RNA of the bacteria Streptococcus B in conventional DCs (cDCs). Human TLR8 reacts to bacterial and viral RNA. The N- and C-terminal portions of human TLR8 remain connected to one another and take part in ligand recognition and dimerization despite the Z-loop between LRR14 and LRR15 being severed, according to structural studies. The dimer undergoes rearrangement upon ligand interaction, bringing the two C termini together [4].

Trafficking of TLRs

All TLRs are created in the ER, go to the Golgi, and are then either attracted to the cell surface or to internal spaces like endosomes. TLRs are assumed to need to be localised inside cells in order to recognise their ligands and avoid coming into touch with self-nucleic acids, which could result in autoimmunity. Intracellular TLRs are transported from the ER to endosomes under the supervision of the multi-pass trans membrane protein UNC93B1. It's interesting to note that UNC93B1 controls excessive TLR7 activation by using TLR9 to block TLR7. Studies on mice carrying the amino acid substitution D34A in UNC93B1 showed that this leads to a phenotype that is hyper responsive to TLR7 and TLR9 and is associated with systemic fatal inflammation that is TLR7-dependent.

As a result, a proposed strategy for controlling autoimmunity is adjusting the balance between TLR7 and TLR9. The ER-resident protein PRAT4A, which controls TLR egress from the ER and their trafficking to the plasma membrane and endosomes, is also responsible for controlling TLR trafficking. The majority of TLRs, including cell surface TLR1, TLR2, TLR4, and TLR5, as well as intracellular TLR7 and TLR9, are generally chaperoned by gp96, a member of the ER-resident heat-shock protein 90 family [5].

Acknowledgement

None.

Conflict of Interest

The author shows no conflict of interest towards this manuscript.

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