Toll-like receptors (TLRs)

Author: V. Dimov, M.D., Allergist/Immunologist, Cleveland Clinic
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

Some Toll-like Receptors (TLRs 2, 4, and 5) are found on the cell surface, where they may bind extracellular PAMPs. Other TLRs (3, 7, 8, and 9) are found within the cells, on endosomal membranes and recognize viruses that have been phagocytosed by cells.

TLRs 3,7,8,9 are found on lysosomes within the cells. They are activated by intracelllular agents (viruses). The pathway is: TLR activation --> kinases --> gene transcription --> TNF, IL-1, INF alpha/beta.

Signaling pattern-recognition molecules, for example, toll-like receptors (TLRs), lead to activation of genes which in turn lead to a specific immune response. TLRs got their name from toll, a membrane receptor in the Drosophila fly which provides resistance to fungi. TLRs are the first point of contact between the immune system and a pathogen.


The curved leucine-rich repeat region of toll-like receptors, represented here by TLR3. Image source: Wikipedia.


Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations. Image source: Wikipedia.

TLR 2
Two
TB and other mycobacteria

TLR4 (for LPS)
CD14

TLR 5
Five
Flagellin
Flagelated bacteria

TLR 7
Seven
SS RNA

TLR 9
Nine
Nonmethylated
Nucleotide motifs - CpG

TLR 3
Three is "Free" of MyD88

TLR9 and MyD88 play central role in protective immunity to malaria http://goo.gl/VVF07

TLRs on the surface of the cells bind surface molecules: flagellin on flagellated bacteria (TLR 5), LPS (TLR 4). Our innate immune system recognizes LPS via the LPS signal transduction pathway, which has the trimolecular complex of CD14/TLR4/MD2 at the core. CD14 was the first described pattern recognition receptor (PAMP receptor).

TLRs inside the cells bind intracellular molecules - nucleic acids: TLR 3, 7, 8, 9.

TLR 3 binds to ds RNA which is never present in humans.

All TLRs except TLR 3 go through MyD88. MyD88 is an abbreviation for Myeloid differentiation primary response gene (88) (MYD88).

Which transcription factors "make" interferon (INF)?
IRF 3 and IRF 7

IRF leads to
INF

There are 12 mammalian TLR genes (11 in humans). All TLRs are membrane glycoproteins. There are 11 different human TLRs, named TLR 1 to 11.

There are 2 groups of TLRs:

- Surface TLRs - for bacteria
- Endosomal TLRs (3, 7, 8, and 9) - for viruses

What are the intracellular TLRs?

TLR 3, 7, 8, and 9 are in the intracellular compartment and detect nucleic acids.

What is MyD88?

MyD88 is an adapter protein that plays a role in TLR signaling. MyD88 is involved in all TLR-signaling pathways except TLR 3.

TLR3 signaling is mediated by toll-interleukin-1-receptor domain containing adapter inducing interferon β (TRIF) and is MyD88-independent.

TLR4 can signal through both MyD88-dependent and independent pathways.



Cytokine receptors (click to enlarge the image)

Medications

TLR agonists, such as imiquimod (TLR 7) and resiquimod (TLR 7 and 8), are used topically for their antiviral and antitumor effects.

SNPs associated with atopic diseases

Filaggrin gene

Filaggrin is essential for epidermal barrier function. SNP associated with eczema and asthma.

17q12-21 gene

ORMDL3 protein defects associated with asthma.

5q22-32 gene

CD14 is a lipopolysaccharide (LPS) receptor. SNPs associated with asthma and atopy.

3p21-22 gene

CCR5 is a chemokine receptor. SNP can be protective against asthma.

Xp22 gene

TLR7 and TLR8 are recognition receptors for viral ssRNA. SNPs assciated with asthma, rhinitis, atopic dermatitis.

5q31 gene

IL-13 is a cytokine that induces IgE secretion, mucus production, and collagen synthesis (fibrosis). SNPs associated with asthma.

ADRB2 gene

ADRB2 gene encodes β2-adrenergic receptor. Argenteum (Arg) or Arg/Arg phenotype associated with decreased albuterol response compared to Gly/Gly phenotype at residue 16.

ADAM33 gene

Type 1 transmembrane protein involved in cell-to-cell interactions. SNPs associated with asthma.

Related reading:

Nickel allergy tracked to a single receptor - Toll-like receptor 4 (TLR4) http://goo.gl/PZic

Related reading

Immunodeficiency and Genetic Defects of Pattern-Recognition Receptors. Mihai G. Netea, M.D., Ph.D., and Jos W.M. van der Meer, M.D., Ph.D. N Engl J Med 2011; 364:60-70, January 6, 2011.

Published: 07/15/2009
Updated: 01/08/2014