Pattern-recognition receptors in human eosinophils

Abstract

The pattern-recognition receptor (PRR) family includes Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs) and the receptor for advanced glycation end products (RAGE). They recognize various microbial signatures or host-derived danger signals and trigger an immune response. Eosinophils are multifunctional leucocytes involved in the pathogenesis of several inflammatory processes, including parasitic helminth infection, allergic diseases, tissue injury and tumour immunity. Human eosinophils express several PRRs, including TLR1-5, TLR7, TLR9, NOD1, NOD2, Dectin-1 and RAGE. Receptor stimulation induces survival, oxidative burst, activation of the adhesion system and release of cytokines (interleukin-1β, interleukin-6, tumour necrosis factor-α and granulocyte-macrophage colony-stimulating factor), chemokines (interleukin-8 and growth-related oncogene-α) and cytotoxic granule proteins (eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase and major basic protein). It is also evident that eosinophils play an immunomodulatory role by interacting with surrounding cells. The presence of a broad range of PRRs in eosinophils indicates that they are not only involved in defence against parasitic helminths, but also against bacteria, viruses and fungi. From a clinical perspective, eosinophilic PRRs seem to be involved in both allergic and malignant diseases by causing exacerbations and affecting tumour growth, respectively.

Figure 1

Schematic outline of the pattern-recognition receptors (PRRs) and their ligands. The Toll-like receptors (TLRs) are located at the cell surface or in endosomes where they sense bacterial proteins and viral nucleic acids, respectively. The nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs) and retinoic acid-inducible gene I (RIG-I) -like receptors (RLRs) are positioned in the cytoplasm where they detect bacterial structures, danger signals and viral RNA. The C-type lectin receptor (CLR) member Dectin-1 is a transmembrane receptor that binds yeast cell wall components, whereas receptor for advanced glycation end products (RAGE) is a transmembrane receptor responsible for the recognition of high-motility group box 1 (HMGB1). All PRRs activate downstream signalling cascades, involving nuclear factor-κB (NF-κB) and interferon (IFN) regulatory factors (IRFs) with the resultant release of pro-inflammatory cytokines and type I IFNs.

Figure 2

Eosinophil responses to pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Eosinophils are activated by various stimuli, leading to increased survival/delayed apoptosis, increased cellular trafficking and production of reactive oxygen species (ROS), pro-inflammatory cytokines, chemokines, granule proteins and leukotrienes, which in turn induce inflammation, airway hyper-reactivity (AHR) and immunomodulation. IL-1β, interleukin-1β; TNF-α, tumour necrosis factor-α; GM-CSF, granulocyte–macrophage colony-stimulating factor; GRO-α, growth-related oncogene-α; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidise; and MBP, major basic protein.