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1Department of Genetics, Behbahan Faculty of Medical Sciences, Behbahan, Iran. 2Faculty of Medicine, Memorial University of Newfoundland, St. John's, ...
Current Immunology Reviews

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Current Immunology Reviews, 2016, 12, 4-9 ISSN: 1573-3955 eISSN: 1875-631X

Emerging Cytokines in Allergic Airway Inflammation: A Genetic Update Karim Daliri1,§, Erfan Aref-Eshghi2,§, Shahrouz Taranejoo3, Shirin Modarresi2, Atefeh Ghorbani2, Ali Nariman1, Mohsen Savaie4, Seyed M.M. Falasiri5, Fatemeh Akhondi-Kharangh6 and Hassan Askari*,7

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Department of Genetics, Behbahan Faculty of Medical Sciences, Behbahan, Iran

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Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Canada

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Department of Chemical Engineering, Monash University, Melbourne, Victoria, Australia

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Department of Anesthesiology and Critical Care Medicine, Faculty of Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Behbahan, Iran

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School of Veterinary Medicine, Islamic Azad University, Kazeroon, Fars, Iran

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Faculty of Medicine, Iran University of Medical Science, Tehran, Iran

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Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran Abstract: Purpose: We aim to discuss the current status of knowledge on the role of recently identified cytokines in airway hyper responsiveness as well as the genetic predisposition conferred by their coding genes to asthma. Methods: We focused on three cytokines and their coding genes,IL-9, IL-17, and IL-22, and conducted a narrative review of all the relevant publications known to the authors. Results: A great body of evidence regarding the involvement of these three cytokines in asthma was discussed and interpreted. These range from studies on the murine models of asthma to clinical and human genetic approaches. Despite the large amounts of information existing on the genetics of IL-9 and IL-17, there is a lacking trend towards the IL-22 genetic studies in asthma. Conclusion: The emergence of new classes of T-helper effector cells and their cytokines has led to a change in our understanding of asthma pathogenesis. This has created both new opportunities and challenges for researchers involved in this field, and is likely to result in improvements and progress in identifying and developing novel therapeutic measures and innovative treatments for asthma.

Keywords: Airway hyper responsiveness, asthma, cytokine, gene. INFLAMMATION AND CYTOKINES IN ASTHMA Asthma, affecting 300 million individuals worldwide, is the most prevalent chronic illness among children and one of the most common allergic conditions in adults [1]. Its prevalence has been on the rise in all western countries [2], and the costs associated with treating asthma have been enormous [1]. The condition is characterized by symptoms of coughing, wheezing, shortness of breath, chest pain or pressure, and physical signs of swift shallow respirations, rapid pulse rate, pallor or cyanosis, hyper-expansion and generalized retractions of the chest, with intra-individual variations in severity and frequency [3]. Asthma is a multifactorial disease that results from a combination of strong genetic and environmental factors. *Address correspondence to this author at the Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran; Tel: +98 9374140937; E-mail: [email protected]  § Equal contribution.

1875-631X/16 $58.00+.00

Twin studies have estimated its heritability to be as high as 92% [4], and many candidate genes have been reported to be associated with asthma [5]. In pathological terms, airway hyperresponsiveness (AHR) and inflammation are the hallmarks of asthma, which are mainly managed by the local immune and constitutional cells in the respiratory tracts [6]. Cytokines produced by these cells control the process by recruiting and activating a cascade of inflammatory cells and factors [7], which direct and modify the inflammatory responses in asthma and likely determine its severity [8]. Traditionally, a specific allergen effector T cells, known as T helper cell type 2 (Th2 or CD4+T type 2), has been considered as the main responsible cell to initiate and mediate the inflammation in asthma. They differentiate into various Th2 cells, further specialize, and produce more specific classes of cytokines following the antigen exposures in the lungs [9]. In other words, asthma is known to be a Th2 mediated disease. Over the past decade, however, it was discovered that the inflammation in asthma is not solely controlled by Th2 cells, but other subtypes of Th cells also contribute to asthma pathogenesis (Fig. 1). Consequently, the cytokines produced © 2016 Bentham Science Publishers

BENTHAM SCIENCE

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Fig. (1). Mechanism of allergic airway inflammation. Exposure of antigen presenting cells (APCs) to allergens leads to the allergen specific activation of T-helper 2 cells (Th) and the production of Ig-E, a major allergic sensitizer. Depending upon the presence of specific cytokines at the time of antigen presentation, naive Th cells (Th0) differentiate into various CD4+ effector T cell subtypes, and secrete various cytokines that mediate and activate the cascade of inflammation. Shortly after, Ig-E sensitized mast-cells release cysteinyl leukotrienes and cytokines which will increase vascular permeability, smooth-muscle contraction, and recruitment of other cells contributing to late onset allergic response (increase in Th2 cells and eosinophils). This will lead to the secretion of pro-inflammatory cytokines including IL-5 and IL13, and basic proteins (eosinophil peroxidase, cationic proteins, and leukotrienes). Although the orchestration of inflammation is mainly believed to be caused by Th2 cells, recent evidence strengthens the role of other Th cells including Th9, Th17, and Th22 in this process. MHC: major histocompatibility complex; TCR: T cell receptor; INFƔ: interferon gamma; TNF: tumor-necrosis factor.

by these cells have gained attractions among the investigators in the field [10]. A query of the terms “cytokines” and “asthma” in the recent medical literature highlights three cytokines as the most studied in the immunopathology of asthma, which include IL-9, IL-17, and IL-22 produced mainly by Th9, Th17, and Th22, respectively [11-13]. In the present review, the importance and significance of these three cytokines in the pathogenesis of allergic airway inflammation will be discussed. We will specifically consider these cytokines as they relate to immunological response, their involvement in AHR, and the genetic susceptibility of their coding genes to asthma. This last aspect is of particular interest, given the large heritability of asthma and the existing evidence for a correlation between genetic polymorphisms of cytokine genes and their plasma levels [14], which has been less frequently reviewed by

scholars. Thus, an update about the genetic studies performed on these cytokines will further contribute towards the objective of this review. IMMUNOPATHOLOGY OF IL-9 IN ASTHMA Interleukin-9 was first introduced as a T-cell and mast cell growth factor in the late 1980s [15], even though it was structurally different from other T-cell growth factors. Fifteen years later, it became known that the major cell type that produces IL-9 is Th9, thus prompting a name change to IL-9 [16-18]. Interleukin-9 is an effector cytokine for various cell types including mast cells, hematopoietic progenitors, B cells, eosinophils, neutrophils and airway epithelial cells, all of which were previously established to be involved in the pathology of asthma and other allergic airway inflammations [19, 20]. These cells proliferate and differentiate after IL-9 stimulation, produce Ig-E and proteases, and over-express

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their Ig-E receptors [21, 22]. IL-9 also increases the number of allergen-induced mast cells in the lung and airways [23]. These changes have been shown in mice to result in a distinct phenotype in the lungs, consisting of increased mucus production, eosinophilic inflammation, and enhanced epithelial collagen sedimentation [24]. Mice that overexpress IL-9 display an increase in AHR after bronchoconstrictor inhalation even without prior sensitization to allergens [24], whereas a lower expression of IL-9 is accompanied by bronchial hyporesponsiveness [25]. Studies involving IL-9 production blockade, or those using IL-9 antagonists in antigen-exposed mice, have reported a reduction in the level of inflammation and a relative improvement in the phenotypic presentations of asthma [26-29], suggesting not only a significant role for IL-9 in airway hypersensitivity, but also a potential therapeutic means for further investigation. Understanding the significance of IL-9 in AHR, however, may not be achievable entirely through murine studies. In contrast to the above findings, mice genetically deficient for IL-9 are not protected against the development of AHR [30]. In addition, the use of alternative strains of mice in various studies and the existence of several contradictory reports are some of the pitfalls in the knowledge available from murine studies. Regardless of these discrepancies, however, studies of human bronchial biopsies from patients with asthma show an elevated expression of both IL-9 and its receptor compared to healthy controls [31]. Correspondingly, two recent phase II clinical trials that tested a humanized monoclonal antibody against IL-9 in patients with asthma reported some evidence of clinical effect [32]. GENETICS OF IL-9 IN ASTHMA Further evidence for the role of IL-9 in AHR comes from genetic association studies in patients with asthma and those suffering from atopic disorders. The IL9 gene is located in 5q31-q33, a chromosomal region containing several important genes for AHR. It was suggested to be a candidate gene for Atopy and AHR based on the finding of an allelic association of an IL9 variant with serum levels of IgE [33]. A GT-repeat polymorphism in the gene was later found to be weakly associated with asthma, with a significantly greater effect (Odds Ratio = 3.33) in the presence of an allergic antigen [34]. Other studies suggested that the associations might be sex-specific. Two single nucleotide polymorphisms (SNPs) in the IL9 gene, rs2069885 and rs2069882, were reported to be associated with polysensitization measures (SPTQ) and lung function values (FEV1/H2, forced expiratory volume in one second divided by the square of height) only in males after Bonferroni’s correction [35]. One of these SNPs (rs2069885) was also reported to be associated with susceptibility to bronchitis due to respiratory syncytial virus infection in infants, with an opposite effect in boys and girls [36]. These results highlight the role of gender and previous environmental exposure in the pathogenesis of the disease. Although these associations provide evidence for the involvement of IL-9 in the pathology of AHR, they remain to be replicated in independent studies with larger sample sizes.

Daliri et al.

IL-17 AND ASTHMA PATHOGENESIS Th17 cells, the main producers of IL-17, differentiate from immature T-cells in the presence of TGF-β, IL-6, IL-1β and IL-23 [37], and are capable of producing a certain number of chemokines and cytokines in addition to IL-17. Th17 cells, however, are not the only source of this interleukin. Six classes of IL-17 (A, B, C, D, E and F) have been recognized to date that are secreted from different cells [38]. Among these, IL-17A and IL-17F, which are produced by Th17, innate lymphoid cells and granulocytes [39], have gained the most attraction in the immunology of AHR. Although the role of IL-17 in several inflammatory diseases had long been recognized, it was not until recently that its concentration was discovered to be increased in the asthmatic airways [12]. This discovery was followed by the detection of IL-17A mRNA overexpression in the sputum of patients with asthma [40]. In addition, several independent reports suggest an important role for IL-17 in bronchial asthma as well as in severe cases of asthma [41, 42]. The IL17 serum level has also shown to be related to the severity of asthma and allergic rhinitis [43]. IL-17A and IL-17F induce airway epithelial cells to secrete CXCL-1 and CXCL-8, leading to neutrophil infiltration [44]. They also enhance IL6 production, which further promotes the activation of Th17 cells [45]. Consistent with this notion, IL-17A protein expression in the sputum from patients with asthma has been positively correlated with neutrophil counts and increased airway reactivity [46]. The adoptive transfusion of cells that secrete IL-17A and IL-17F into mice followed by an ovalbumin challenge led to increased neutrophil recruitment in lungs [47]. In ROR-ƔT transgenic mice the challenge also increased neutrophilic inflammation compared to wild-type mice [48]. These findings together suggest that Th17 cells may in fact be involved in a type of asthma which presents with an overpopulation of neutrophils rather than eosinophilia, and is less responsive to corticosteroid therapy [49]. These findings point out the importance of disease classification based on the type of inflammatory cytokines for the purposes of diagnosis, management, and development of potential therapeutic agents in asthma. IL-17 may be involved not only in the development of AHR, but also in periodic asthma attacks and its exacerbations. The great majority of asthma exacerbations occur following viral infections. IL-17A levels in lungs have been associated with increased susceptibility to this phenomenon [50]. The exact mechanism of this occurrence is not entirely clear; however, allergen-exposed mice are reported to have a decreased IL-17A protein expression following respiratory syncytial virus infection compared to non-infected mice [51]. Thus, it can be concluded that the mechanism of action for IL-17A in AHR varies depending on the presence or absence of viral infection, a subject that requires further scrutiny. Despite the availability of fundamental knowledge about the action of IL-17, the mechanism through which IL-17 and Th17 cells participate in allergic airway inflammation is not completely understood. Conflicting reports of both proinflammatory and anti-inflammatory effects for IL-17A on

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AHR have been published in the literature [52]. Further clarification of this issue may emerge from the therapeutic targeting of IL-17 receptors in ongoing clinical trials of treatments for asthma [44]. IL-17 AND GENETICS OF ASTHMA Genetic studies have also attempted to explain the potential mechanism of IL-17 in AHR. The earliest report in the literature is an inverse genetic association between an H161R variant located in the third exon of the IL17F gene and the risk of asthma among 867 Japanese subjects [odds ratio = 0.06 (95% confidence interval: 0.01-0.43)] [53]. The variant appears to block IL-8 expression in vitro [53]. A Korean study reported an association between the rs1889570 SNP, located in the promoter of the same gene, and both asthma susceptibility and peripheral blood eosinophil counts in patients with asthma [54]. In a Chinese population, rs763780 in IL17F was reported to be associated with asthma only in males [55]. Individuals heterozygous for rs17880588 in IL17A were significantly more common among control group in a Saudi Arabian population, who also showed an up-regulation of both Il17A and IL17F [56]. In a Taiwanese population, rs8193036 in IL17A promoter showed a weak association with pediatric asthma [57]. In another Chinese study an IL17 SNP, rs2275913, was reported to be associated with several asthma-related traits including susceptibility to asthma, abnormal lung function, serum total Ig-E levels in individuals with asthma, and susceptibility to bronchiolitis as well as the rates of Streptococcus pneumoniae and Moraxella catarrhalis detection [58]. Although these studies attempted to unravel the genetics of IL-17 in asthma, the existing information is disperse and inconclusive since none of the variants reported has ever been replicated and their mechanisms of action remain vague. These reports, however, provide some fundamental clues about the role of IL-17 in AHR, which pave the road for future studies. IL-22 AND ALLERGIC AIRWAY INFLAMMATION T-helper cells, particularly Th1, Th17 and Th22, are the main source of IL-22 production; however, other immune cell types such as cytotoxic T cells, natural killer T (NK) cells, and RORγt + innate lymphoid cells have also been reported to be able to secrete this cytokine [59-61]. IL-22 has been reported to be involved in host defense as well as the pathogenesis of a variety of autoimmune diseases such as psoriasis, rheumatoid arthritis and inflammatory bowel disease [62]. The role of IL-22 in AHR is thought to be of a complex one. Evidence suggests both pro-inflammatory and antiinflammatory effects for IL-22 in AHR, and its mechanism of action is not restricted to its effects on the immune system. Consistent with a pro-inflammatory role, it has been detected in bronchoalveolar lavage fluid in murine asthma models [63, 64], and its expression is increased in peripheral blood mononuclear cells in patients with asthma [65, 66] as well as in the lungs of antigen sensitized mice [67]. On the other hand, IL-22 attenuates antigen-induced eosinophilic inflammation in the airways, possibly by controlling the expression of other AHR related cytokines [68]. IL-22 blockade is known to intensify the secretion of major

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modulators of Th2 response and infiltration [69, 70], and to inhibit the IFN--induced expression of pro-inflammatory chemokines and adhesive molecules in human bronchial epithelial cells [71]. These reports along with the existence of a negative correlation between the levels of IL-22 and pro-inflammatory chemokines in plasma [72] are consistent with an anti-inflammatory function for IL-22 in AHR. The fact that IL-22 can influence AHR through alternative pathways other than inflammation, adds to the complexity of the issue. The IL-22 receptor is widely expressed by airway smooth muscle cells, upon the activation of which, the cells exhibit increased proliferation and migratory activities, resulting in airway hyperplasia and remodelling [70-73], which are two of the key pathological observations in AHR. Therefore, the role of IL-22 in asthma may involve disruption of the balance between its anti-inflammatory and hyperplasic effects in the airways. These points show that more investigation is required to better understand the mechanism of action for this interesting interleukin in AHR. INSIGHTS ON THE HUMAN GENETIC STUDIES OF IL-22 IN ASTHMA Considering the significant role of IL-22 in AHR, the gene coding for IL-22 would be the perfect candidate gene to study AHR and asthma. However, despite the numerous reports of genetic associations between the IL22 gene and a variety of autoimmune and inflammatory conditions, no such association has been found for asthma. This begs for more studies to be done on the genetic association of IL22 gene and asthma, which would shed new light on the mechanism of IL-22 in AHR. CONCLUDING REMARKS AND FUTURE PERSPECTIVES Although the role of Th2-mediated immune responses in the pathology of AHR has been well established, the emergence of new classes of Th effector cells and their cytokines has led to a reconsideration of our current understanding of AHR pathogenesis. This has created new opportunities for investigating the mechanism of development of asthma, a condition associated with high morbidity worldwide. The knowledge available to date on this matter, however, is insufficient and its interpretation is difficult due to the existence of conflicting reports. Moreover, very little is known about the genetic basis of these new factors. Unravelling these issues will undoubtedly strengthen our current understanding of Asthma and it will pave the way to identify and develop novel therapeutics measures and treatments. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS We thank Ms. K. Shashok (Author AID in the Eastern Mediterranean) for improving the use of English in the manuscript.

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Revised: April 9, 2015

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cytokine structurally related to IL-10 and inducible by IL-9. J Immunol 2000; 164(4): 1814-9. Liang SC, Tan XY, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006; 203(10): 2271-9. Cella M, Fuchs A, Vermi W, et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 2008; 457(7230): 722-5. Pan HF, Li XP, Zheng SG, Ye DQ. Emerging role of interleukin-22 in autoimmune diseases. Cytokine Growth Factor Rev 2013; 24 (1): 51-7. Lajoie S, Lewkowich IP, Suzuki Y, et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol 2010; 11(10): 928-35. Schnyder B, Lima C, Schnyder-Candrian S. Interleukin-22 is a negative regulator of the allergic response. Cytokine 2010; 50(2): 220-7. Farfariello V, Amantini C, Nabissi M, et al. IL-22 mRNA in peripheral blood mononuclear cells from allergic rhinitic and asthmatic pediatric patients. Pediatr Allergy Immunol 2011; 22(4): 419-23. Zhu J, Cao Y, Li K, et al. Increased expression of aryl hydrocarbon receptor and interleukin 22 in patients with allergic asthma. Asian Pacific J Allergy Immunol 2011; 29: 266-72. Taube C, Tertilt C, Gyulveszi G, et al. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease. PLoS ONE 2011; 6: e21799. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol 2011; 12(5): 383-90. Oral HB, Kotenko SV, Yılmaz M, et al. Regulation of T cells and cytokines by the interleukin10 (IL10)family cytokines IL19, IL 20, IL22, IL24 andIL26. Eur J Immunol 2006; 36(2): 380-8. Hirose K, Takahashi K, Nakajima H. Roles of IL-22 in allergic airway inflammation. J Allergy (Cairo) 2013; 2013: 260518. Pennino D, Bhavsar PK, Effner R, et al. IL-22 suppresses IFN-mediated lung inflammation in asthmatic patients. J Allergy Clin Immunol 2013; 131(2): 562-70. Chang Y, Al-Alwan L, Risse PA, et al. TH17 cytokines induce human airway smoothmuscle cell migration. J Allergy Clin Immunol 2011; 127(4): 1046-53. Kudo M, Melton AC, Chen C, et al. IL-17A produced by ab T cells drive airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med 2012; 18: 547-54.

Accepted: May 28, 2015