Toll-like receptors (TLRs): functions, types, and pathology

Localization and molecular targets

Toll-like receptors are strategically located on cells that are the first to come into contact with potential infectious agents. First and foremost, they are abundant in leukocytes performing the function of patrolling the body. In addition, the receptors are widely represented in barrier tissues: the epithelium of the digestive tract, the vascular endothelium, skin keratinocytes, and microglial cells.

The main task of TLRs is to detect pathogen-associated molecular patterns (PAMPs). These are evolutionarily conserved structures of microorganisms that are vital for pathogens but completely absent in the human body. Key types of PAMPs include:

Lipopolysaccharides (LPS), which form the basis of the outer membrane of Gram-negative bacteria.
Lipoteichoic acids, characteristic of Gram-positive microorganisms.
Peptidoglycans of the bacterial wall.
Specific nucleic acids: bacterial DNA and viral RNA.

Signal transduction and the role of the CD14 glycoprotein

To ensure that the recognition of Gram-negative bacteria is as accurate and efficient as possible, the participation of the specific CD14+ glycoprotein is required. Cells that express it (monocytes, tissue macrophages, dendritic cells, and activated granulocytes) are capable of providing an extremely high affinity of the complex between bacterial LPS and the Toll-like receptor.

The binding of TLRs to PAMPs is the starting point for a powerful intracellular response. With the obligatory participation of adapter proteins, a signaling cascade is triggered that leads to the following events:

Activation of the crucial nuclear transcription factor NF-kB occurs.
The activated factor enters the nucleus and triggers the expression of genes encoding pro-inflammatory cytokines.

The ultimate effects of this cascade are aimed at a full-scale launch of the immune response. Phagocytic cells are activated, the work of T- and B-lymphocytes is stimulated, and the synthesis of protective immunoglobulins (Igs) is manifold increased.

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Receptor specificity to pathogens

Innate immunity is able to differentiate threats due to the strict specificity of receptors. Depending on which infectious agent has entered the body, various types of TLRs are expressed on the surface of immune cells. This makes it possible to select the most appropriate defense scenario.

Gram-positive bacteria: recognized predominantly by the TLR2 receptor, which reacts to their structures.
Gram-negative bacteria: identified using TLR4, tuned to detect lipopolysaccharides.
Viral infections: induce the expression of the widest range of receptors, including TLR1, TLR2, TLR3, TLR7, TLR8, and TLR9, which react to viral components.

TLR system pathology and immunodeficiencies

Since Toll-like receptors act as a fundamental element of innate immunity, any defects in their operation inevitably lead to increased susceptibility of the body to infectious diseases (IDs).

There are two main causes of such disorders:

Direct mutations in genes encoding the TLR receptors themselves.
Congenital defects in the intracellular signal transduction factors from the receptor to the nucleus.

In clinical practice, mutations of the TLR4 gene, specifically the Asp299Gly and Thr399Ile genetic variants, are of particular importance. The pathogenesis of these mutations consists in the formation of an insufficient, weakened response to bacterial lipopolysaccharide. The consequences for the patient can be quite serious: a significantly more frequent development of infectious diseases caused by Gram-negative microbes is observed, along with a high risk of developing severe bronchiolitis.

Briefly: answers to topical questions

What is the molecular structure of a Toll-like receptor (what domains does it include)?

The molecular structure of a Toll-like receptor includes extracellular, transmembrane, and cytoplasmic domains.

LRR domain — forms the extracellular part, the binding site of which has a horseshoe shape (the outer part is formed by α-helices, the inner by β-sheets).
Transmembrane segment — located between the LRR and TIR domains, responsible for selecting the membrane type and embedding into it.
TIR domain (Toll/IL-1 receptor and resistance domain) — represents the cytoplasmic (C-terminal) part, consists of a central β-sheet and five α-helices, and performs the function of interacting with adapter molecules.

Which specific adapter proteins are involved in the intracellular signal transduction from TLRs?

Adapter proteins that interact with the intracellular TIR domain are involved in signal transduction from Toll-like receptors:

MyD88 — in the MyD88-dependent pathway with the participation of TIRAP, it acts as a "bridge" between the active TLR dimer and the first signaling kinase; this pathway is used by all TLRs except TLR3, while TLR4 uses both signaling pathways.
TIRAP — participates in the MyD88-dependent pathway together with MyD88.
TRIF — participates in the TRIF-dependent pathway; this pathway is indicated for TLR3, and for TLR4, the use of both signaling pathways is specifically noted.
TRAM — indicated among the adapter proteins with which the TIR domain interacts.
Mal — indicated as an adapter protein in the MyD88-dependent pathway using TLR4 as an example.

Which specific pro-inflammatory cytokines are synthesized after NF-kB activation via TLRs?

As a result of the activation of the transcription factor NF-kB via Toll-like receptor signaling pathways, the expression of pro-inflammatory cytokine genes is triggered.

In the provided sources, among the specific cytokines synthesized as a result of this process, only one is explicitly named:

Tumor necrosis factor (TNF).

The names of other specific pro-inflammatory cytokines produced directly after NF-kB activation via TLRs are not detailed in the text.

How to memorize

To remember bacterial specificity, use the rule: Gram(-) bacteria have a complex wall with LPS — they need a receptor with a higher number (TLR4). Gram(+) bacteria are structured differently — TLR2 is sufficient for them.

Class and exam questions

What are PAMPs and how do they relate to TLRs?

PAMPs are pathogen-associated molecular patterns, i.e., typical conserved microbial structures (such as LPS or bacterial DNA). Toll-like receptors physically bind to them to recognize the infection and trigger an immune response.

Why is the CD14+ glycoprotein needed?

It is necessary to create a high affinity of the complex between lipopolysaccharide (LPS) and the receptor. CD14+ is expressed on monocytes, macrophages, activated granulocytes, and dendritic cells.

What does a mutation in the TLR4 gene lead to?

Mutations such as Asp299Gly cause a weak immune response to LPS. Because of this, the patient suffers more frequently from infections caused by Gram-negative flora and has a high risk of developing severe bronchiolitis.

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What else to study on this topic

Structure and types of pathogen-associated molecular patterns (PAMPs)
The role of adapter proteins in TLR signal transduction
Mechanisms of nuclear transcription factor NF-kB activation
Features of CD14+ expression on various leukocyte types
Pathogenesis of severe bronchiolitis in innate immunity defects

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Toll-like Receptors