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Mini Scheme: Eosinophilia

Biological basis and clinical implications of immunological molecules involved in eosinophilic inflammation in allergic rhinitis, chronic rhinosinusitis, and asthma

Shin KariyaDepartment of Otolaryngology–Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JapanCorrespondence[email protected]
,
Mitsuhiro OkanoDepartment of Otolaryngology–Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
&
Kazunori NishizakiDepartment of Otolaryngology–Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Article: 26601 | Received 10 Nov 2014, Accepted 14 Jan 2015, Published online: 17 Feb 2015

Abstract

Eosinophils are specialized and multifunctional immune cells that are involved in both protection and pathology in human health and disease. Eosinophils have been thought to play an important role in parasitic infection, and defense against parasites is one of the main functions of eosinophils. Eosinophils also have damaging effects on the pathogenesis of numerous diseases, especially allergic disorders. A large number of inflammatory mediators including cytokines, chemokines, and adhesion molecules are associated with the development and chemotaxis of eosinophils. Allergic rhinitis and asthma are typical respiratory diseases with eosinophilic inflammation, and eosinophils are also involved in the onset and development of some types of chronic rhinosinusitis. The purpose of this review is to summarize the physiology of eosinophils and to discuss potential therapeutic targets related to eosinophils in allergic rhinitis, chronic rhinosinusitis, and asthma.

Eosinophils are a type of white blood cell produced in the bone marrow and are particularly involved in immune responses to allergic inflammation and parasitic infection. Since the discovery regarding the capacity of causing tissue damage by eosinophil-derived granule proteins, eosinophils have become recognized as one of the main players in the immune system. Eosinophils also have the ability to synthesize a variety of inflammatory mediators and play an important role in homeostatic mechanisms.

Eosinophils play an important role in pathophysiology in upper and lower respiratory diseases including allergic rhinitis, chronic rhinosinusitis, and asthma Citation1–(Citation5). Allergic rhinitis is a typical type 1 [immunoglobulin (Ig) E-mediated] hypersensitivity immune response to environmental allergens. Eosinophilic infiltration of the nasal mucosa and subepithelial edema are characteristic features of allergic rhinitis. The presence of eosinophils in nasal secretions is an important finding in the diagnosis of allergic rhinitis. Chronic rhinosinusitis is usually classified into three categories: chronic rhinosinusitis without nasal polyposis (CRSsNP), chronic rhinosinusitis with nasal polyposis (CRSwNP), and allergic fungal rhinosinusitis (AFRS) (Citation3, Citation6, Citation7). Eosinophilia is more commonly associated with CRSwNP than with CRSsNP, and recent studies show that CRSwNP and CRSsNP have disparate clinical features based on distinct inflammatory pathways, cytokine profiles, and different tissue remodeling Citation8–(Citation19). AFRS is a non-invasive form of fungal rhinosinusitis that represents an allergic hypersensitivity disorder (IgE mediated in some cases) (Citation20). The presence of allergic mucin in the sinonasal cavity containing fungal hyphae and a large number of degranulating eosinophils is a significant finding in AFRS (Citation21, Citation22). Asthma is a common but complex disease involving type I hypersensitivity reactions (Citation23). Eosinophils and Th2 cytokines such as interleukin (IL)-4, IL-5, and IL-13 play an important role in the pathophysiology of asthma. Chemokine (C-C motif) ligand (CCL) 11 (also known as eotaxin-1), CCL24 (also known as eotaxin-2), and CCL26 (also known as eotaxin-3) derived from epithelial cells mediate eosinophil recruitment into the asthmatic lung under the influence of cytokines such as IL-13 (Citation24).

The similarity of anatomical and immunological findings in the upper and lower airway has been reported, and numerous studies show a close relationship between sinonasal diseases and lower respiratory diseases Citation25–(Citation31). The purpose of this review is to summarize the role of eosinophils in allergic rhinitis, chronic rhinosinusitis, and asthma, as well as to describe recent advances in the therapeutic targets related to eosinophils in the management of allergic rhinitis, chronic rhinosinusitis, and asthma.

Differentiation of eosinophils

Eosinophils are produced in bone marrow from pluripotent stem cells. In regulating eosinophil development, IL-3, IL-5, granulocyte–macrophage colony-stimulating factor (GM-CSF), and several transcription factors including GATA-1 (a zinc finger family member), PU.1 (an Ets family member), and CCAAT/enhancer-binding protein (c/EBP) family members (c/EBPα, c/EBPβ, and c/EBPɛ) are particularly important factors, and synergistically regulate activity (Citation32, Citation33). In these transcription factors, GATA-1 is clearly the most important in specifying eosinophil lineage. The experimental study reveals that mice with a targeted deletion of the high-affinity GATA-binding site present in the GATA-1 promoter gene show loss of the eosinophil lineage (Citation34); these findings are supported by eosinophil differentiation experiments in vitro (Citation35, Citation36). IL-3 and GM-CSF also induce the proliferation of neutrophils and basophils and are not relatively specific for the development of eosinophils. However, IL-5 potently and specifically stimulates eosinophil production in bone marrow (Citation37).

Adhesion and migration of eosinophils

Eosinophil migration from bone marrow into circulating blood is primarily regulated by IL-5 (Citation38). Under normal conditions, most eosinophils in peripheral organs are found in the gastrointestinal tract except the esophagus, mammary gland, uterus, and thymus. Among these organs, the gastrointestinal eosinophil is predominant (Citation39). In healthy individuals, eosinophils in the gastrointestinal tract are regulated by the interaction between CCL11 and its receptor [CCR3, chemokine (C-C motif) receptor 3] and are present independent of adaptive immunity and enteric flora (Citation40, Citation41). Under baseline condition, eosinophils in the thymus, mammary gland, and uterus are also controlled by CCL11 (Citation42).

Several molecules, including a number of cytokines (IL-4, IL-5, and IL-13), adhesion molecules (β1-, β2-, and β7-integrins), RANTES (regulated on activation, normal T-cell expressed and secreted, also known as CCL5), eotaxins, intercellular adhesion molecule 1 (ICAM-1, also known as CD54), vascular cell adhesion molecule 1 (VCAM-1, also known as CD106), and mucosal addressin cell adhesion molecule 1 (MadCAM-1) are involved in the trafficking of eosinophils into inflammatory sites and adhesion of eosinophils in endothelial cells Citation43–(Citation49). In addition, a recent study shows that the CD2 subsets of immunoglobulin superfamily co receptors (CD48/2B4) have an important role in human eosinophil adhesion and intercellular adhesion, and CD48 is a useful marker for the severity of eosinophilic inflammation (Citation50). The eotaxin/CCR3 axis has a central regulatory role in allergic airway inflammation (Citation51, Citation52). Tissue eosinophils can likely survive for at least two weeks based on in vitro observations (Citation44). Of the cytokines implicated in modulating leukocyte recruitment, only IL-5 and the eotaxins selectively regulate eosinophil trafficking (Citation53).

Eosinophil activation

Human eosinophils are activated by many different molecules including IL-3, IL-4, IL-5, IL-13, and GM-CSF (Citation54, Citation55). A Th1-type cytokine, interferon-gamma (IFN-γ), and cytokines derived from the epithelium, such as IL-33 and thymic stromal lymphopoietin (TSLP), also stimulate human eosinophils Citation56–(Citation59). In addition to endogenous receptors, human eosinophils also express receptors for pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), including the family of Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs: NOD1 and NOD2), retinoic acid-inducible gene I-like receptor (RIG-I), C-type lectin receptor (Dectin-1), and the receptor for advanced glycation end products (RAGE) (Citation60, Citation61). Human eosinophils are reported to express TLR-1, 2, 3, 4, 5, 6, 7, 9, and 10. These TLRs recognize a wide variety of products that are expressed or produced by microbes Citation62–(Citation67). For example, ligands for TLR-2 (peptidoglycan), TLR-5 (flagellin), and TLR-7 [imiquimod (R837)] induce eosinophil activation and the release of inflammatory mediators (Citation62, Citation68). Proteases are frequently found in microbes and allergens, and human eosinophils are capable of recognizing proteases including serine protease, aspartate protease, and cysteine protease. Eosinophils activated by proteases demonstrate the active release of pro-inflammatory mediators Citation69–(Citation72). The role of fungi in the development of asthma is well known, and β-glucan, a major fungal cell wall component, activates eosinophils via the β2 integrin molecule (CD18) pathway (Citation33, Citation73). Human eosinophils also recognize damaged tissue/cell components and endogenous molecules induced from tissue injury, including uric acid, adenosine triphosphate (ATP), high mobility group box (HMGB)-1, and S100 calcium-binding protein family members, resulting in tissue homeostasis Citation74–(Citation76).

Eosinophil granule proteins

Eosinophil cytoplasm contains large specific granules that are the principal identifying feature of eosinophils. Activated eosinophils release granule-stored cationic proteins (MBP, major basic protein; ECP, eosinophil cationic protein; EPO, eosinophil peroxidase; and EDN, eosinophil-derived neurotoxin), which exert a range of biological effects on host cells and microbial targets.

MBP is a small cytotoxic protein and is one of the principal and specific proteins present in eosinophils. It is implicated in many pathological conditions including direct cytotoxic effects, allergic reactions, parasitic infections, and stimulation for a variety of cells to produce inflammatory molecules. MBP is classified as two homologs (MBP-1 and MBP-2) encoded by two different genes. MBP-1 is an arginine- and cysteine-rich polypeptide (13.8 kDa) composed of 117 amino acids. MBP-1 is highly toxic to parasites, bacteria, and mammalian cells by disrupting the lipid bilayer membrane or altering the activity of enzymes within tissues (Citation77, Citation78). MBP-2 is less potent than MBP-1 in in vitro biological activities. However, MBP-2 is present only in eosinophils and may be a useful biomarker for eosinophil-associated diseases (Citation79).

ECP is a basic secretion protein involved in the immune response system. ECP also belongs to the RNase A superfamily and is known as ribonuclease 3 (RNase-3). The cDNA sequence for ECP codes for a preprotein of 160 amino acids and a protein of 133 amino acids. The molecular weight of ECP ranges between 16 and 21.4 kDa (Citation32, Citation80). ECP has marked toxicity for a variety of helminth parasites, hemoflagellates, bacteria, single-stranded RNA viruses, and host tissues (Citation81). In vitro, ECP plays a beneficial role in host defense against single-stranded RNA respiratory syncytial virus (Citation82). ECP is also active against both Gram-negative and Gram-positive strains of bacteria by the mechanism of toxicity involving both the bacterial cell wall and the cytoplasmic membrane (Citation78). The bacterial agglutinating activity of ECP is driven by the formation of amyloid-like aggregates at the bacterial cell surface (Citation83). These recent findings suggest that the amyloidogenic behavior of ECP participates in antibacterial host responses to infection, and that the biophysical property of bactericidal N-terminal peptides of ECP is the novel therapeutic target in the development of antimicrobials (Citation84).

EPO is a two-chain protein and is a major enzyme present in eosinophils. The light chain has a molecular mass of 11–15 kDa and the heavy chain a molecular mass of 50–57 kDa (Citation32). EPO is the abundant cationic matrix protein of the specific granule; human eosinophils have 12 µg of EPO per cell (Citation85). EPO catalyzes the formation of cytotoxic oxidants implicated in asthma, allergic inflammatory disorders, and cancer. Oxidant production begins with the generation of superoxide by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzymatic system, and the superoxide dismutates into hydrogen peroxide (H2O2) (Citation86). H2O2 is converted by EPO to highly reactive halogenating acids, such as hypobromous acid (HOBr), hypochlorous acid (HOCl), or xanthine oxidase (XO) (Citation87). In addition to the ability to produce oxidants, EPO has some cytotoxic effects as a cationic toxin in parasites and mammalian cells in the absence of H2O2 and a halide co-factor. Furthermore, EPO exerts both anti-inflammatory and pro-inflammatory activities Citation88–(Citation91) .

EDN, also known as RNase-2, is a member of the ribonuclease A superfamily and is a single-chain polypeptide with an observed molecular mass of 18.6 kDa (Citation92). EDN is localized in the matrix of the secondary granule of the eosinophil, but is also detected in mononuclear cells and neutrophils (Citation93). EDN plays a protective role in respiratory syncytial virus infection in the bronchial tract (Citation94, Citation95). In addition, EDN induces the migration and maturation of dendritic cells. Recent studies show that EDN is an endogenous ligand of TLR-2 and can activate dendritic cells and monocytes/macrophages by triggering the TLR-2-myeloid differentiation factor 88 (Myd88) signaling pathway, resulting in enhanced antigen-specific Th2-biased immune responses and cytokine production (IL-5, IL-6, IL-10, and IL-13) (Citation96, Citation97).

Among these eosinophil granule proteins, MBP and ECP were extensively examined. Serum ECP concentration can be used as a marker of local and systemic eosinophil expression (Citation98). MBP and ECP have the clinical importance in monitoring eosinophilic activity in allergic rhinitis, chronic rhinosinusitis, and asthma Citation99–(Citation102).

Eosinophils in innate and adaptive immunity

Human eosinophils have the ability to secrete a large number of important inflammatory and regulatory factors including cytokines, chemokines, and growth factors, and express numerous receptors (Table and ) (Citation43, Citation93) (Citation103–Citation107). Eosinophils modulate the immune response in both the innate or non-specific immune system and the adaptive or specific immune system.

Table 1 Inflammatory molecules and growth factors generated by human eosinophils

Table 2 Receptors expressed by human eosinophils for cytokines, chemokines, and lipid mediators

In the innate immunity system, eosinophils primarily have a defensive role against large, non-phagocytosable organisms and fungi by the production of cationic proteins, cytokines, and chemokines. However, the excessive reaction in activated eosinophils sometimes has harmful effects on humans, and direct activation of eosinophils by microbe-derived molecules exacerbates allergic inflammation following bacterial and/or viral infections (Citation38). Innate immunity serves as the first line of defense against infection, and pattern recognition receptors including TLR constitute an important class of immune recognition receptors that can recognize pathogenic molecules. Expression of several TLRs in eosinophils has been reported, and the TLR-7 system may represent an important mechanism for host defense against viral infections Citation62–(Citation65). Proteases from various microbes and allergens, such as house dust mites and fungi, induce production of several inflammatory mediators through a family of G-protein-coupled protease-activated receptors (PAR), and human eosinophils constitutively transcribe mRNA for PAR-2 and PAR-3 (Citation69, Citation108, Citation109). Eosinophils have multifunctional β2 integrin molecules (also known as CD18) that recognize β-glucan, a major cell wall component of fungus, and release their cytotoxic granule proteins into the extracellular milieu and onto the surface of fungal organisms, killing the fungus in a contact-dependent manner (Citation110, Citation111).

Antibodies are the key components of adaptive immunity, and eosinophils play a significant role in adaptive immune responses thorough Fc receptors including FcαR, FcγR, and FcɛR. In addition, a large number of adhesion molecules and receptors are involved in the activation and degranulation of eosinophils () (Citation43, Citation93, Citation103, Citation104, Citation112, Citation113). The Fc receptor for IgA (FcαR, also known as CD89) is expressed in human eosinophils, and IgA2 is a highly potent stimulus for eosinophil killing of Schistosoma mansoni (Citation114). IgG is also considered to be involved in eosinophil activation via FcγR pathways, both in human and mouse (Citation115, Citation116). IgG, platelet-activating factor (PAF), and GM-CSF stimulate human eosinophils, and increase eosinophil adhesion by activating integrins. Among these integrins, αMβ2 integrin (also known as Mac-1, CR3, or CD11b/CD18) and α4β1 integrin (also known as VLA-4 or CD49d/CD29) play a critical role for eosinophil granule protein release Citation117–(Citation119). IgE plays a critical role in respiratory diseases related to allergic reactions including asthma, allergic rhinitis, and chronic rhinosinusitis. Both the high-affinity IgE receptor (FcɛRI) and the low-affinity IgE receptor (FcɛRII, also known as CD23) are found in eosinophils. FcɛRI in eosinophils from patients with eosinophilia induce various functions of eosinophils, including degranulation and parasite cytotoxicity (Citation120).

Table 3 Adhesion molecules, complement receptors, immunoglobulin (Ig) receptors, and members of Ig superfamily related to human eosinophils

Therapeutic targets related to eosinophils in allergic rhinitis

Allergic rhinitis is a common disease. Its pathophysiology is based on IgE-mediated type I hypersensitivity. Inhaled allergens binding to dendritic cells and mast cells in the upper airway initiate an immune-inflammatory process in allergic rhinitis. Dendritic cells located in the nasal mucosa capture the allergens and act as antigen-presenting cells. In sensitized individuals, allergens deposited onto the nasal mucosa bind the allergen-specific IgE to the surface of mast cells resulting in rapid release of inflammatory mediators such as histamine (Citation1). Histamine, tumor necrosis factor α (TNF-α), and lipid mediators such as leukotriene C4 and prostaglandin D2 contribute to the influx of eosinophils into the upper airway by stimulation of the expression of adhesion molecules (ICAM-1, VCAM-1, and E-selectin) in the vascular endothelium, and induce late allergic responses such as nasal obstruction (Citation1, Citation121). IL-5 also plays a key role in eosinophilic inflammation in allergic rhinitis through the transendothelial migration of eosinophils from circulating blood to the mucosal tissue in the upper airway and eosinophil survival in tissue.

A number of available therapies are recommended in several guidelines including ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines for a step-wise approach to the management of allergic rhinitis (Citation26). Currently available pharmacological agents, immunotherapy, and other therapeutic options for allergic rhinitis include antihistamines, corticosteroids, antileukotrienes, nasal decongestants, mast cell stabilizers, anticholinergic agents, allergen-specific immunotherapy, monoclonal anti-IgE antibody, capsaicin desensitization, and complementary treatments (Citation2).

Glucocorticoids inhibit the production of cytokines including IL-5 and GM-CSF by glucocorticoid receptor agonism and anti-inflammatory action through multiple effects. Glucocorticoids can shorten the half-life of eosinophils and reduce eosinophil survival in nasal tissue. Glucocorticoids also reduce nasal lavage eosinophilia. The long-term use of systemic corticosteroids induces adverse effects including inhibition of growth in children, disturbances of metabolism, glaucoma and cataract formation, immunosuppression, skin thinning, behavioral abnormalities, and osteoporosis (Citation122). However, administration of intranasal steroids is relatively safe, and the efficacy of topical steroid therapy exceeds the risk of any systemic side effects (Citation123).

Leukotrienes are a family of inflammatory lipid mediators synthesized from arachidonic acid in macrophages, mast cells, and eosinophils. Among the leukotrienes, leukotriene C4, leukotriene D4, and leukotriene E4 have the ability to contract the bronchial smooth muscles and cause eosinophil locomotion, mucous production, edema, and increased vascular permeability (Citation124). In addition, leukotriene D4 increases P-selectin-dependent leukocyte rolling flux and eosinophil adhesion through β2-integrin expression in eosinophils (Citation125, Citation126). The production and the physiological activity of leukotrienes are inhibited by blocking their receptors or specific enzymes. Cysteinyl leukotriene 1 receptor antagonist (montelukast) is a useful drug for treating allergic rhinitis. However, montelukast is less effective than intranasal corticosteroids.

Mast cells are an important therapeutic target in the treatment of allergic rhinitis. In sensitized patients, Fc receptors and specific IgE antibodies in mast cells can rapidly recognize the previously met allergen, and activated mast cells synthesize and degranulate mediators such as histamine, tryptase, leukotrienes, proteases, cytokines (IL-1, IL-3, IL-4, IL-5, IL-13, TNF-α), and chemokines (IL-8, GM-CSF, MCP-1, RANTES). Intranasal cromolyns are able to inhibit the degranulation of mast cells and the migration or survival of eosinophils resulting in the inhibition of both early and late phases of allergic reactions. Cromolyns can prevent as well as treat the symptoms of allergic rhinitis Citation127–(Citation129) .

A large body of evidence regarding the pathways and factors involved in allergic rhinitis suggests possible therapeutic agents for novel management of allergic rhinitis. These factors, which have been extensively examined, include glucocorticoid receptor agonists, histamine receptor antagonists, prostaglandin D2 receptor antagonists (CRTH2 antagonists), phosphodiesterase 4 inhibitors, bradykinin B2 receptor antagonists, MAP kinase inhibitors, human neutrophil elastase inhibitors, cytokine synthesis inhibitors, α4β1 integrin antagonists, tryptase inhibitors, ion channel blockers, nitric oxide synthase inhibitors, TLR signaling mediators, and a member of the CD2 subset of the immunoglobulin superfamily receptors (CD244, also known as natural killer cell receptor 2B4) blocker (Citation2, Citation130). For example, prostaglandin D2 is one of the major cellular regulators synthesized from arachidonic acid and plays an important role in development and maintenance of allergic response including recruitment of eosinophils (Citation131, Citation132). CRTH2 receptor antagonists are promising agents for the treatment of chronic allergic diseases including allergic rhinitis (Citation133, Citation134). Several orally active CRTH2 antagonists are under clinical development (Citation135).

Therapeutic targets related to eosinophils in chronic rhinosinusitis

Chronic rhinosinusitis is usually divided into three subtypes: CRSsNP, CRSwNP, and AFRS (Citation136). The cytokine profile of CRSsNP is mainly Th1 dominant, and the inflammatory cell infiltration is made up of mostly neutrophils, with a low percentage of eosinophils, mast cells, and plasma cells. In contrast, patients with CRSwNP have a predominantly Th2-biased eosinophilic inflammation, and AFRS is defined as chronic rhinosinusitis accompanied by allergic mucin containing degranulated eosinophils and fungal hyphae, and IgE-mediated fungal allergy (Citation3, Citation6, Citation7). CRSwNP is associated with increased levels of IL-4, IL-5, IL-13, RANTES, CXCL8, ECP, eotaxin, GM-CSF, VEGF, IgE, ICAM-1, VCAM-1, E-selectin, P-selectin, matrix metalloproteinase (MMP)-1, MMP-2, MMP-7, MMP-9, and Th2-associated transcription factor (GATA-3). These factors play a significant role in the 1) development and activation of eosinophils, 2) downregulation of eosinophilic apoptosis, and 3) eosinophil infiltration in sinonasal sinus mucosa (Citation8, Citation9, Citation14, Citation137–Citation145). CRSwNP is more likely than CRSsNP to be associated with asthma and aspirin-exacerbated lower respiratory disease (Citation7). A close relationship between CRSwNP and Th2-biased eosinophilic inflammation has been reported. However, because CRSwNP sometimes shows neutrophil-dominant inflammation, an analysis of the specific inflammatory pattern (neutrophilic or eosinophilic) may be necessary to adequately treat patients with CRSwNP (Citation146).

Medical treatments for chronic rhinosinusitis include nasal saline irrigation, topical steroid nasal sprays (intranasal glucocorticoids), systemic antibiotics, systemic glucocorticoids, topical steroid irrigations, long-term macrolide treatment, topical antibiotic treatment, antileukotriene treatment, and aspirin desensitization therapy (Citation3). A European position paper on rhinosinusitis and nasal polyps 2012 (EPOS 2012) recommends intranasal glucocorticoids, nasal saline douche, and bacterial lysates for CRSsNP and intranasal glucocorticoids and systemic glucocorticoids for CRSwNP (Citation6). Glucocorticoids and antileukotriene have a significant effect on eosinophilic inflammation in patients with chronic rhinosinusitis, and antileukotriene agents may be used as an adjunct to topical glucocorticoids in the treatment of CRSwNP Citation147–(Citation149).

Monoclonal antibody therapy is one of the immunotherapies using monoclonal antibodies to specifically bind to target cells or proteins. Omalizumab, a humanized recombinant monoclonal anti-IgE antibody, reduces circulating levels of IgE, FcɛRI expression on mast cells, respiratory tissue eosinophilia, and production of GM-CSF and Th2 cytokines (IL-4, IL-5, and IL-13) (Citation150). A meta-analysis shows that omalizumab is associated with statistically significant symptom relief, decreased rescue medication use, and improvement of quality of life in patients with inadequately controlled allergic chronic rhinosinusitis (Citation151). In addition, a recent double-blind placebo control study showed that mepolizumab, a humanized monoclonal anti-IL-5 antibody, reduces the size of nasal polyps (Citation152). IgE and/or IL-5 inhibition may be considered as a potential novel therapeutic approach in patients with chronic rhinosinusitis with severe eosinophilic inflammation (Citation153). However, EPOS 2012 does not recommend monoclonal antibody therapy for patients with chronic rhinosinusitis (Citation6). The safety and efficacy of monoclonal antibody therapy for chronic rhinosinusitis is under investigation.

There is much debate regarding the role of fungi in chronic rhinosinusitis. Although a significant role of fungi in sinonasal sinus in the majority of chronic rhinosinusitis cases has been suggested, prospective, double-blind, placebo-controlled multicenter clinical trials show that topical amphotericin B treatment has no significant effect on the level of inflammatory mediators and outcome of CRSsNP and CRSwNP Citation154–(Citation156). AFRS, as well as CRSsNP and CRSwNP, is an established subtype of chronic rhinosinusitis, and the diagnostic criteria consist of the following: 1) nasal polyposis, 2) fungi on staining, 3) eosinophilic mucin without fungal invasion into sinus tissue, 4) type I hypersensitivity to fungi, and 5) characteristic radiological findings with soft tissue differential densities on CT scanning (Citation6). Eosinophils play a central role in the onset and development of AFRS. Oral and topical steroids following endoscopic sinus surgery are recommended to control eosinophilic inflammation in AFRS, and the usefulness of antifungal immunotherapy for AFRS has been reported (Citation6, Citation157).

Therapeutic targets related to eosinophils in asthma

Asthma is a complex and heterogeneous disease with several clinical subtypes. It is often detected in patients with upper respiratory diseases including allergic rhinitis and chronic rhinosinusitis (Citation158, Citation159). Because an increase of eosinophils in the respiratory tissues and peripheral blood and the overexpression of eosinophil-related inflammatory factors are characteristic findings of most asthma phenotypes, the eosinophil is considered to be the central effector cell responsible for airway inflammation in asthma. Eosinophils have the potential to injure airway tissues through the release of granule-associated basic proteins (which damage nerves and epithelial cells), lipid mediators (which cause bronchoconstriction and mucus hypersecretion), and reactive oxygen species (which generally injure mucosal cells) (Citation93). Serum ECP levels can be used as a clinical tool for estimating eosinophil inflammatory activity in asthma and are also related to disease severity (Citation78).

Inhaled corticosteroids are the recommended drug for patients with asthma. The first choice as add-on therapy to inhaled corticosteroids is an inhaled long-acting β2 agonist (Citation160). Inhaled corticosteroids strongly inhibit Th2 cytokine release and Th2-driven eosinophilic airway inflammation (Citation161). Inhaled β-agonists are effective at reversing bronchoconstriction in asthma by protein kinase A-dependent relaxation of airway smooth muscle (Citation162). The appropriate combination of long-acting β2 agonist and inhaled corticosteroid medications is still an important issue, and a recnet cohort study shows that asthma exacerbation is lower for budesonide–formoterol combination therapy versus fluticasone–salmeterol combination therapy due to lower rates of oral corticosteroid use and asthma-related emergency department visits, which indicate better treatment effectiveness of those patients initiated with budesonide–formoterol combination therapy compared with fluticasone–salmeterol combination therapy (Citation163). Because the clinical response to inhaled corticosteroids is variable, the biomarkers in asthmatic patients predicting clinical responsiveness to inhaled corticosteroids therapy are intensively examined (Citation164).

The potential agents in the treatments for difficult asthma include anti-IgE antibody, anti-IL-4 antibody, anti-IL-5 antibody, anti-IL-13 antibody, anti-IL-4 receptor antibody, anti-CXCR2 antibody, and leukotriene receptor blockers Citation165–(Citation167). Omalizumab therapy is an alternative for patients with more severe poorly controlled asthma (Citation168). Mepolizumab significantly reduces asthma exacerbations and is associated with improvements in markers of asthma control (Citation169). A recent meta-analysis shows that the addition of tiotropium may be beneficial for patients with poorly controlled asthma (Citation170). In addition, novel targets in the treatment for asthma such as tyrosine kinase inhibitors, IFN-α, ICAM-1, VCAM-1, integrin, eotaxin/CCR3 pathway, CRTH2, and immune inhibitory receptors on eosinophils [sialic acid-binding immunoglobulin-like lectin (Siglec)-3, Siglec-7, Siglec-8, Siglec-10, FcγRII, CD85a, and CD300a] are intensively examined for future therapeutic uses (Citation4, Citation32, Citation43, Citation48, Citation93, Citation113, Citation171, Citation172).

Conclusion

Eosinophils are the most important cells involved in the pathophysiology of allergic rhinitis, chronic rhinosinusitis, and asthma. It is also likely that eosinophils play an important role in airway remodeling and inflammation through TGF-β and other inflammatory mediators. Corticosteroids are the most potent and widely used drugs to control eosinophilic inflammation in both the upper and lower airways. However, steroid-resistant eosinophilic inflammation in the airway has also been reported (Citation122, Citation173). Several promising agents are under development to increase the number of therapeutic options against eosinophil-associated inflammation. Further studies are needed to characterize molecular mechanisms underlying eosinophilic airway inflammation in each subtype of the diseases.

Conflict of interest and funding

The authors have no conflict of interest to disclose.

Acknowledgements

This work was supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research) (Grant Number 25462642).

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