When the allergy alarm bells toll: The role of Toll-like receptors in allergic diseases and treatment

Abstract

Toll-like receptors of the human immune system are specialized pathogen detectors able to link innate and adaptive immune responses. TLR ligands include among others bacteria-, mycoplasma- or virus-derived compounds such as lipids, lipo- and glycoproteins and nucleic acids. Not only are genetic variations in TLR-related genes associated with the pathogenesis of allergic diseases, including asthma and allergic rhinitis, their expression also differs between allergic and non-allergic individuals. Due to a complex interplay of genes, environmental factors, and allergen sources the interpretation of TLRs involved in immunoglobulin E-mediated diseases remains challenging. Therefore, it is imperative to dissect the role of TLRs in allergies. In this review, we discuss i) the expression of TLRs in organs and cell types involved in the allergic immune response, ii) their involvement in modulating allergy-associated or -protective immune responses, and iii) how differential activation of TLRs by environmental factors, such as microbial, viral or air pollutant exposure, results in allergy development. However, we focus on iv) allergen sources interacting with TLRs, and v) how targeting TLRs could be employed in novel therapeutic strategies. Understanding the contributions of TLRs to allergy development allow the identification of knowledge gaps, provide guidance for ongoing research efforts, and built the foundation for future exploitation of TLRs in vaccine design.

Tolerogenic dendritic cells and TLR4/IRAK4/NF-κB signaling pathway in allergic rhinitis

“…TLRs are 1 class of transmembrane proteins synthesized in the endoplasmic reticulum ( 52 , 53 ). TLRs, sensing damage-associated molecular patterns (DAMPs) as well as PAMPs, can initiate signaling in both innate and adaptive immune pathways ( 54 , 55 ).…”

“…Upregulation of tolDCs and Tregs favors allergen-specific IgG production and induces immune tolerance, which may inhibit IgE activity and basophil activation ( 86 ). The protective allergen-specific IgG4 produced by Tregs competes with IgE for allergen binding to prevent IgE-mediated allergic reactions ( 52 ). TolDCs with high expression of IL-10 inhibit Th1 differentiation and limit effector T cell function, thereby suppressing allergic inflammation and promoting allergen-specific tolerance ( 41 ).…”

“…With abundant leucine repeats, TLRs regulate Th1/Th2 immune balance through DCs, mast cells and Tregs ( 52 , 60 ). The adaptive immune response can be skewed toward Th1 by TLRs, which can cause DCs maturation and T cell activation ( 60 ).…”

“…Activation of DCs by allergens results in Th1/Th2 imbalance, which contributes to the development of AR. Genetic factors, environmental factors, and allergens themselves all influence the role of the TLRs in AR ( 52 ). TLRs agonists with well-defined immunomodulatory properties, favoring anti-allergic T lymphocyte responses and also increasing IL-10 production to prevent Th1 and Th17 responses ( 37 , 96 ).…”

“…TLR4 can initiate, exacerbate, or prevent allergic diseases ( 66 ). Generally, TLR4 is expressed at low levels and is upregulated once activated by allergens or other factors ( 52 ). TLR4 protein expression levels are elevated in the nasal mucosa of individuals with AR ( 96 ).…”