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RHINITIS, SINUSITIS AND UPPER AIRWAY DISEASE: Edited by Ruby Pawankar and David P. Skoner

Targeting IL-25 as a novel therapy in chronic rhinosinusitis with nasal polyps

Lee, Mingyua,b,g; Kim, Dae Wooc,d; Shin, Hyun-Wooa,b,d,e,f,g

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Current Opinion in Allergy and Clinical Immunology: February 2017 - Volume 17 - Issue 1 - p 17-22
doi: 10.1097/ACI.0000000000000332
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Abstract

INTRODUCTION

Chronic rhinosinusitis with nasal polyps (CRSwNP) is recognized as a heterogeneous inflammatory disease of the sinonasal tracts and nasal cavities that shows with a prevalence of 5–10% worldwide [1–3]. Environmental factors and host contributions, such as bacterial infection, inhaled allergens, pollutants, anatomical obstruction of the osteomeatal complex and defective epithelial barrier functions, are related to the pathogenesis of CRSwNP [4,5▪▪,6▪]. Furthermore, emerging evidence suggests that a spectrum of inflammatory cell and T-cell patterns are associated with exacerbation or induction of upper airway disorders [4,7]. However, the cause and pathogenesis of CRSwNP remain incompletely understood.

CRSwNP has long been considered to be an eosinophil-dominant Th2 inflammatory condition, especially in Western countries [8], and eosinophil infiltration represents a hallmark of Th2 skewing, according to interactions between several chemokine receptors produced by airway epithelial cells [9]. Recent reports suggest that the epithelial cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 exert effects on Th2-type adaptive responses and ILC2s [10▪▪]. IL-25, one of the IL-17 family of cytokines, has been identified as a key component in the induction and modulation of Th2 inflammatory processes [11]. Indeed, IL-25 regulates multiple aspects of mucosal immunity by promoting Th2 polarization of naïve CD4+ T cells, enhancing inflammation via the production of IL-4, IL-5, and IL-13 [12]. More recently, an important role for IL-25 in modulating the development and function of ILC2 was reported [13,14]. Additionally, we demonstrated that a neutralizing antibody that targeted IL-25 reduced the number of polyps and the inflammatory status in a murine nasal polyp model [15▪▪]. Because IL-25's roles in Th2 inflammation have recently been revealed, there are few reports regarding anti-IL25 treatment, especially in association with nasal polyposis. This review focuses on recent publications on nasal polyps in relation to IL-25, and suggests the possibility of IL-25 as a therapeutic target. Detailed information on ongoing clinical studies in nasal polyps can be found at https://clinicaltrials.gov/. 

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TH2-PROMOTING CYTOKINES IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS: THYMIC STROMAL LYMPHOPOIETIN, IL-33, AND IL-25

Roles of thymic stromal lymphopoietin and IL-33 in chronic rhinosinusitis with nasal polyps

As described above, type 2 cytokines, including IL-4, IL-5, and IL-13, are believed to modulate inflammation in the pathogenesis of eosinophilic CRSwNP [4,16]. Type 2 cytokines can be produced by several immune cells, including T helper 2 cells, mast cells, eosinophils, basophils, and ILC2s, in both innate and adaptive immune responses [17,18▪]. Recent findings have suggested that several newly identified cytokines, including TSLP, IL-33, and IL-25, are secreted primarily by epithelial cells and contribute to type 2 immunity [19]. This will lead to type 2 inflammatory disorders, including atopic dermatitis, asthma, and CRSwNP, without any specific immune activation through innate lymphoid cells (ILCs) [19–21]. In particular, ILC2s promote acquired immune responses by facilitating Th2 lymphocyte differentiation [22▪]. Thus, targeting these key cytokines that are responsible for Th2 immunological responses may offer effective strategies for reducing Th2 inflammation and disease burden.

TSLP, an IL-7-like cytokine, induces type 2 inflammation; its mRNA was shown to be elevated in eosinophilic nasal polyps [23–27]. TSLP has been reported to play a pathogenic role in CRSwNP. However, the underlying mechanism of induction remains largely undefined because of a lack of commercially available detection systems. The production of TSLP by epithelial cells is known to be controlled by both innate and adaptive immune signaling via activation of Toll-like and cytokine receptors [20,28,29]. Kouzaki et al.[30] demonstrated that a protease receptor is an initiator of TSLP production. This suggests that TSLP may play a role in early activation at the initial site of exposure in the epithelium. TSLP modulates the differentiation of naïve T cells into effector Th2 cells by increasing the expression of OX40 ligand (OX40L) on the dendritic cells that interact with the OX40 receptor on CD4 T cells [24].

Furthermore, TSLP enhances the function and activity of ILC2, which have large numbers of TSLP surface receptors [31]. Nagarkar et al.[32] showed that a cleaved form of TSLP might have higher activity than full-length TSLP, cleaved by the incubation of TSLP and nasal polyp tissue extract. Importantly, Gauvreau et al.[33] reported that AMG 157, a human anti-TSLP monoclonal antibody (mAb), reduced allergen-induced early and late asthmatic responses by binding to human TSLP. On the basis of literature reports, TSLP may be an important modulator in eosinophilic nasal polyps.

IL-33, the latest member of the IL-1 cytokine family, induces allergic airway inflammation and has also been reported to have analogous functions in the presence or absence of an adaptive immune response. The secretion of IL-33 is known to be regulated by P2 purinergic receptors [34]. In the case of CRS, the mRNA levels of IL-33 and IL-33 receptors were highly upregulated in nasal mucosa, but not in nasal polyps or other inflamed areas in CRSwNP [35,36]. Importantly, IL-33 also activates ILC2s and augments the production of IL-13, a key regulator that induces type 2 inflammation [37]. Thus, several groups have shown that blockade of IL-33 and its known receptors, ST2 and IL-1RAcP, attenuates allergic airway inflammation in a murine model of allergic asthma [38–40]. Similarly to trials on TSLP, phase I clinical trials are also ongoing on AMG 282, a mAb that binds and inhibits the ST2 receptor, and may be useful for treating CRSwNP [5▪▪]. Given that IL-33 drives type 2 inflammation in Rag-deficient mice [41], IL-33 may also contribute to allergic asthma and CRSwNP; thus it could be a potential pharmacological target.

IL-17 FAMILY MEMBERS: TARGETING IL-17E (IL-25)

IL-17E and signaling mechanisms

Among the IL-17 family members, IL-17A is the most recently defined cytokine, and is produced by the T helper 17 subset of CD4+ cells [42]. Five additional structurally related cytokines have also been discovered: IL-17B, IL-17C, IL-17D, IL-17F, and IL-17E, also known as IL-25 [43]. Among these family members, IL-25 is the most distinct cytokine in terms of structure, and is considered to be important for both acquired and innate immune responses; this is in contrast to the other IL-17 family members, which are related to neutrophil recruitment and proinflammatory cytokine induction. IL-25 is produced by Th2 cells, mast cells, eosinophils and, primarily, by epithelial cells [11]. It also triggers type 2 inflammatory responses via upregulation of the IL-25 surface receptor on Th2 cells, with the simultaneous recruitment of eosinophils and secretion of Th2 cytokines. We reported elevated expression of IL-25 in the mucosa of CRSwNP patients. Moreover, its elevation was associated with the upregulation of the IL-25 receptor (IL-17RB) found on inflammatory cells [15▪▪]. IL-25 is preformed and stored in extra-nuclear cellular compartments of epithelial cells [44]. It is then released as a result of both environmental stimuli, such as proteases, papain, trypsin, and house dust mite (HDM) allergen proteases, as well as defective barrier function (unlike IL-33, which is stored in the nucleus [10▪▪,44]). For these reasons, IL-25 may also belong to the ‘alarmins’ family. Among the five IL-17R family molecules (IL-17RA to IL-17RE), the heterodimers IL-17RA and IL-17RB serve as receptors for IL-25 [45]. Indeed, IL-25 binds only to IL-17RB. However, considering that both IL-17RA (/) and IL-17RB (/) mice do not show Th2 immunity [46], both chains play roles in signal transduction. After IL-25 binding, Act 1 is recruited to the SEFIR domain of IL-17RB [47]. Then, in the cytoplasmic domain of IL-17RB, the TRAF-6-binding motif binds directly binds with complexes consisting of TRAF6 and TAK1, and this activates downstream pathways, including NF-κB, MAPK-AP-1, and C/EBP [48].

IL-25: a key modulator in the development of Th2 inflammatory diseases

Recent research advances have provided new insight into Th2-type responses, by introducing several newly identified cytokines that are involved in innate immunity. Among them, the IL-17-related cytokine IL-25 is possibly associated with Th2 inflammation and can promote Th2 cell differentiation. Type 2 inflammation is typically characterized by increased levels of related cytokines, including IL-4, IL-5, and IL-13, as well as activation of CD4+ Th2 cells, plasma cells secreting IgE, eosinophils, and mast cells that protect against microorganisms [17,49▪▪]. It has been reported that several allergens, such as ragweed and fungal proteases, can trigger IL-25 mRNA expression in lung epithelial cells [50]. Kato [51▪▪] recently demonstrated that the combination of calprotectin, S100A8 and S100A9 protein complexes, and ATP triggered the secretion of TSLP and IL-25 in NHBE cells. However, whether IL-25 is induced by specific microorganisms is unclear.

Until now, whether the level of IL-25 was upregulated in nasal polyps has been controversial. Lam et al.[52] demonstrated that IL-25 mRNA levels were significantly upregulated in ethmoid sinuses of CRSwNP patients versus healthy controls and patients with CRSsNP. We also show that the levels of IL-25 and IL-25R, both mRNA and protein, were elevated in nasal polyp tissues from patients with CRSwNP [15▪▪]. Lam et al.[53▪] recently reported that IL-25 receptor (IL-17RB)-expressing Th2 effector cells were detected in nasal polyp tissues, indicating that IL-25 may contribute to Th2 inflammation in patients with CRSwNP. Moreover, upregulation of IL-25, both mRNA and protein, in nasal polyp tissues was found in Asian patients with CRSwNP [15▪▪], and correlated with worse Lund–Mackay computed tomography (CT) scores and blood eosinophilia [52]. Serum levels of IL-25 were also much higher in allergic patients with asthma versus normal controls [54]. In contrast, Miljkovic et al.[55] showed that IL-25 mRNA was decreased markedly in nasal polyps versus the ethmoid sinuses of control and CRSsNP patients. Kato [49▪▪] reported that IL-25 was not an important modulator of type 2 inflammation in CRS; their data showed that mRNA levels of IL-25 were very low in sinuses and the level of IL-25 mRNA did not differ much between nasal polyps and healthy sinus tissues.

Furthermore, few researchers have shown the presence of IL-25 protein in CRS. Linuma et al.[56▪▪] detected IL-25 upregulation only in E-CRS patients. Liao et al.[57▪] showed that protein levels of IL-25 and IL-17RB were increased significantly in both E-NP and NE-NP. Given that nasal polyps of Asian populations are less eosinophilic versus those of Western patients, the significant differences might have been due to the composition of the major inflammatory cell population. Although levels of IL-25 in CRSwNP remain controversial, most studies have shown that IL-25 is upregulated in patients with CRSwNP, and that it plays a role in the pathogenesis of nasal polyp formation. Thus, blocking IL-25 could be an effective therapeutic strategy for nasal polyp patients with high levels of IL-25.

ILCs are an emerging family of cells that seem to have important roles in tissue remodeling and innate immune responses against microorganisms. These cells were recently characterized and may be involved into type 2 inflammatory diseases, but they account for a small proportion of the total population of immune cells. ILCs are characterized by a lack of known lineage markers and an absence of receptors for specific pathogens. Like T helper cells, ILCs can be divided into three subsets depending on the cytokines produced; ILC1, ILC2, and ILC3 [58,59]. Among these, ILC2s secrete large quantities of type 2 cytokines. Indeed, ILC2s were originally identified in mice in 2010, by several groups [60], and were finally characterized in humans in 2011 [61]. Importantly, ILC2s express IL-25R, IL-33R, and TSLP-R on their cell surfaces, facilitating type 2 cytokine secretion [62]. In inflammatory conditions, the combination of IL-33 and TSLP synergistically increases the secretion of type 2 cytokines in human ILC2s isolated from nasal polyps [63]. This indicates that ILC2s may contributes to type 2 inflammation in eosinophilic nasal polyps by responding to IL-33 and TSLP. Apart from IL-33 and TSLP, IL-25 also contributes to the activation of ILC2s. Elevation of ILC2s has now been confirmed in US, Australian, and Asian populations [36,55,64]. Furthermore, Matsushita et al.[65▪] reported that proallergic cytokines from epithelial cells and ILC2s played essential roles in allergic nasal diseases. Taken together, the elevation of IL-25 due to pathogenic conditions is associated with ILC2s and contributes to the pathogenesis of nasal polyps.

Effect of anti-IL-17E in nasal polyps and other Th2 inflammatory diseases

Despite evidence for an association between IL-25 and CRSwNP, clinical trials using anti-IL-25 antibodies have not been conducted yet. We first reported the therapeutic effects of anti-IL-25 in a Staphylococcal enterotoxin B (SEB)-induced murine nasal polyps model and found that IL-25 was upregulated in nasal polyp tissues from patients with CRSwNP, and in nasal epithelium in the SEB-induced nasal polyp murine model. Blocking IL-25 inhibits Th2 inflammation by reducing local inflammatory cytokines and nasal polyp formation capacity [15▪▪]. Apart from IL-25 in association with nasal polyps, some studies have shown effects of anti-IL-25 in vitro, as well as in animal models of asthma and ulcerative colitis, both of which are Th2 inflammatory disorders. Gregory et al.[66] confirmed that blocking IL-25 reduced Th2-based inflammatory cytokines in an HDM-induced asthma model. Camelo et al.[67] demonstrated upregulation of IL-25 in a oxazolone-induced intestinal colitis model, and also showed that an IL-25-neutralizing antibody improved the clinical condition. Additionally, Ballantyne et al.[68] blocked IL-25 signaling using a mAb against IL-25 and prevented airway hyperresponsiveness, an effect accompanied by reduced levels of Th2-associated cytokines. Moreover, IL-25 (/) mice displayed reduced lung pathology in an asthma model [68] and delayed Th2-related cytokine production during helminth infection [69]. Given these reports suggesting IL-25 as a therapeutic target in the pathogenesis of CRSwNP and other related Th2-based inflammatory diseases, we believe anti-IL-25 has potential utility in ongoing therapies against CRSwNP.

CONCLUSION

In this review, we focused primarily on IL-25 and its association with Th2 inflammation, especially in CRSwNP. Furthermore, we suggest the potential of IL-25 as a therapeutic target in CRSwNP. Anti-IL-25 treatment reduced Th2-associated inflammatory markers and overall inflammatory status, as evidenced by in-vitro and in-vivo experiments. It attenuated epithelial disruption and reduced nasal polyp numbers in a SEB-induced murine nasal polyp model. Additionally, recent clinical approaches have shown favorable effects of monoclonal antibodies against TSLP and IL-33 in eosinophilic nasal polyp. This suggests that they may be novel therapeutic targets for CRSwNP. Given that patients with CRSwNP have also been reported to show elevated levels of IL-25, anti-IL-25 therapy could be a meaningful strategy to improve clinical results in patients with nasal polyposis.

Acknowledgements

None.

Financial support and sponsorship

This work was supported by a National Research Foundation of Korea grant funded by the Korea government (MEST) (NRF-2013R1A1A1006980).

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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Keywords:

allergy; chronic rhinosinusitis; IL-25; nasal polyps; therapeutic target

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