Allergology International 69 (2020) 412e416

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Allergology International

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Review Article Implications of IL-13Ra2 in atopic skin inflammation

* Masutaka Furue a, b, c, , Dugarmaa Ulzii a, Takeshi Nakahara a, b, Gaku Tsuji a, c, Kazuhisa Furue a, Akiko Hashimoto-Hachiya a, c, Makiko Kido-Nakahara a a Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan b Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan c Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka, Japan article info abstract

Article history: Atopic dermatitis (AD) is a common eczematous skin disorder characterized by skin inflammation, Received 20 October 2019 barrier disruption, chronic pruritus and marked scratching. Th2 , especially IL-13, play a Received in revised form pathogenic role in AD. IL-13 signals via a heterodimeric receptor composed of IL-4Ra and IL-13 Ra1. A 6 January 2020 second receptor, IL-13 Ra2, binds to IL-13 with high affinity, but it works as a decoy receptor. IL-13 Ra2is Accepted 8 January 2020 overexpressed in the lesional skin of AD. Notably, mechanical scratching, as well as IL-13 itself, also Available online 6 February 2020 upregulates IL-13 Ra2 expression. The scratch-induced IL-13 Ra2 upregulation may attenuate the IL-13- mediated epidermal barrier dysfunction and dermal fibrosis. Recent studies stress an importance of Keywords: IL-13Ra2 another IL-13 Ra2 ligand, 3-like 1 or YKL-40 in Th2 differentiation. However, the implications of IL-13 increased IL-13 Ra2 levels remain elusive in AD. In this review, we summarize the recent topics on IL- Atopic dermatitis 13 Ra2 in atopic skin inflammation. Scratch Copyright © 2020, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access YKL-40 article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction receptor a (IL-4Ra) antibody dupilumab, which inhibits both IL-4 and IL-13 signals.18 Atopic dermatitis (AD) is a common eczematous skin disorder IL-4 and IL-13 are encoded by adjacent and share a characterized by skin inflammation, barrier disruption and chronic common receptor and signaling pathway.19 However, IL-4 and IL-13 pruritus that manifests heterogeneous clinical phenotypes.1,2 The are differentially expressed in vivo by a number of different cells barrier dysfunction allows the colonization of Staphylococcal that regulate innate and adaptive immunity. For example, lymph aureus.3 Intense pruritus deteriorates work productivity and so- node T follicular helper cells, which regulate B cell immunity, ex- cioeconomic stability, induces sleep disturbance and lowers quality press IL-4 but not IL-13.19 Basophils and invariant natural killer T2 e of life for afflicted patients.1,4 9 Itch-induced scratching appears to cells also express IL-4, whereas mucosal group 2 innate lymphoid exacerbate skin inflammation by accelerating cellular damage in cells express mostly IL-13 and little IL-4.19 Notably, more recent, the lesional skin.10 The itch-scratch cycle clinically induces large-scale transcriptomic analysis revealed the specific and “lichenification”, which manifests microscopically as epidermal dominant role of IL-13 in the lesional skin of AD because IL-4 acanthosis and dermal fibrosis.11,12 expression was nearly undetectable.20 Consistent with this Since the discovery of type 2 helper T (Th2) cells by Mosmann notion, the anti-IL-13 antibody tralokinumab successfully et al., in 1986,13 type 2 cytokines, such as IL-4 and IL-13, have played improved AD.21 Compounding evidence suggests that IL-4 plays an e critical roles in allergic inflammation in AD.14 17 The pathogenic important role in humoral responses, while IL-13 mediates tissue importance of interleukin (IL)-4 and IL-13 has recently been sug- responses and may have pathogenic dominance in the develop- e gested by an excellent treatment response of AD to the anti-IL-4 ment of AD.19 21 IL-13 signaling is capable of enhancing itch sensation.22 IL-13 downregulates the skin barrier function by inhibiting the expres- sion of terminal differentiation molecules such as filaggrin and e involucrin.23 25 It also stimulates dendritic cells and fibroblasts to produce CCL17 and CCL22, which recruit CCR4þ Th2 cells into the * Corresponding author. Department of Dermatology, Graduate School of Medical local tissue.26,27 Moreover, IL-13 is a profibrotic and is Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan. responsible for AD-related fibrosis.11,12 E-mail address: [email protected] (M. Furue). Peer review under responsibility of Japanese Society of Allergology. https://doi.org/10.1016/j.alit.2020.01.005 1323-8930/Copyright © 2020, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). M. Furue et al. / Allergology International 69 (2020) 412e416 413

IL-13 Ra2 signaling and localization levels compared with those of wild-type mice.35 These results suggest that IL-13 Ra2 serves as a protective or negative regulator The IL-13 signaling is regulated via a complex receptor system. against IL-13-induced allergic inflammation.35 In nonhematopoietic cells, IL-13 engages a heterodimeric receptor composed of IL-4Ra and IL-13 Ra1.19,28 IL-13 Ra1 binds IL-13 with IL-13 Ra2 and the itch-scratch reaction low affinity; however, when it forms a complex with IL-4Ra,it binds with much higher affinity, inducing the effector functions of Itch-induced scratching appears to aggravate ear swelling in IL-13.19,28 A second receptor, IL-13 Ra2, is closely related to IL- murine contact hypersensitivity because protection of the ear from 13 Ra1. IL-13 Ra2 binds IL-13 with high affinity, but its cytoplasmic scratching by a plastic collar significantly reduced skin inflamma- region is short, lacks known signaling motifs and does not function tion.10 Although epidermal IL-13 Ra2 is overexpressed in AD as a signal mediator.19 Cells with high IL-13 Ra2 expression can compared with normal skin,42 the effects of scratching on IL-13 Ra2 rapidly and efficiently deplete extracellular IL-13.29 Likewise, IL-13 expression remain undetermined. We examined IL-13 Ra2 responses are enhanced in mice lacking IL13RA2.30 These studies expression in confluent keratinocyte cultures with or without have highlighted that IL-13 Ra2 can act as a scavenger or decoy scratching by plastic tip.42 Notably, scratch injury selectively receptor for IL-13 and elicits antagonistic activity against IL-13.19 upregulated the expression of IL-13 Ra2 but not IL-4Ra and IL- Both keratinocytes and fibroblasts express functional IL-4Ra, IL- 13 Ra1 in human keratinocytes. IL-13 also upregulated the e 13 Ra1 and IL-13 Ra2.23,31 35 expression of IL-13 Ra2, but not IL-4Ra and IL-13 Ra1. In addition, The binding of functional heterodimeric IL-4Ra and IL-13 Ra1by scratch injury synergistically augmented IL-13-induced IL-13 Ra2 IL-13 induces the activation of downstream Janus kinase 2 (JAK2) expression.42 The IL-13 Ra2 protein expression was confined to the and tyrosine kinase 2 (TYK2).36 JAK2 activates signal transducer scratch-edge area. The scratch-induced IL-13 Ra2 expression was and activator of transcription 3 (STAT3), and TYK2 activates STAT6 negated in the presence of the ERK/MEK inhibitor U0126 and the and STAT1.36 After binding with IL-13, IL-13 Ra2 is internalized but p38 MAPK inhibitor SB203580 but not by the JNK inhibitor is unable to activate the STAT6 pathway, which is essential for SP600125. IL-13 inhibited the expression of involucrin in the un- atopic inflammation.37 Another proposed mechanism is that the treated HaCaT keratinocyte cell line, whereas the IL-13-induced short cytoplasmic domain of IL-13 Ra2 can bind to the cytoplasmic involucrin downregulation was attenuated in the IL-13 Ra2- domain of IL-4Ra and interfere with its signal transduction.38 overexpressing HaCaT cells.42 These results reinforce two issues. IL-13 Ra2 exists in both membrane-bound and soluble forms. In First, IL-13 Ra2 works as the decoy receptor for IL-13 in keratino- mice, discrete transcripts generated by alternative splicing encode cytes. Second, mechanical scratching does induce contradictory soluble and membrane-bound forms of IL-13 Ra2.39,40 In contrast, biological impacts on skin. Scratching exacerbates skin inflamma- the human soluble form of IL-13 Ra2 is generated by enzymatic tion but simultaneously triggers a reactive compensatory response cleavage of the membrane-bound form by matrix metal- against excess amounts of IL-13 by upregulating the decoy IL- loproteinase 8.41 Both membrane-bound and soluble forms of IL- 13 Ra2(Fig. 1). 13 Ra2 exert decoy functions.28 Anti-IL-4Ra antibody dupilumab interferes with both IL-4 and IL-13 signaling and is very efficacious for AD.18,45 It is reported that IL-13 Ra2 and atopic dermatitis the elevated expression of IL-13 Ra2 is rapidly normalized in lesional skin in parallel with clinical improvement by dupilumab The expression of IL-13 Ra2 is augmented by IL-13, IL-4, and treatment.45 As dupilumab inhibits both IL-13 signals and pruritus, tumor necrosis factor-a (TNF-a) but not by interferon-g (IFN-g)in we assume that dupilumab may downregulate both IL-13-induced human keratinocytes.35,42 TNF-a synergizes the IL-13-induced or and scratch-induced IL-13 Ra2 expression. IL-4-induced IL-13 Ra2 upregulation in keratinocytes.35 In contrast to keratinocytes, IFN-g, IL-13 and IL-4 enhance IL-13 Ra2 expres- IL-13 Ra2 and fibrosis sion in human bronchial epithelial cells.43 Notably, the expression level of IL-13 Ra1 is stable and is not affected by these cytokines in IL-13 is a pro-fibrotic cytokine that may play a crucial role in keratinocyte and bronchial epithelial cells.35,42,43 Silencing of IL- fibrosis or remodeling in atopic inflammation.33,34,47 When IL-13 13 Ra2 in the human HaCaT keratinocyte cell line significantly and IL-4 are neutralized independently, it emerges that IL-13 is increased IL-13-mediated STAT6 activation compared with those the dominant cytokine in driving fibrosis.47 Intratracheal instilla- transfected with control small interference RNA, which again in- tion of bleomycin induced pulmonary fibrosis.28 The pulmonary dicates the decoy nature of IL-13 Ra2 for IL-13.35 fibrosis was decreased in the lung that was adenovirally transfected Microarray analysis of keratinocytes cultured from AD patients with IL-13 Ra2.28 Moreover, IL-13 upregulated collagen and TGF-b1 and normal controls revealed an overexpression of IL-13 Ra2in production in fibroblasts but not in IL-13 Ra2-transfected fibro- AD.44,45 Laser capture microdissection analysis followed by blasts.28 These results indicate that IL-13 Ra2 acts as a decoy re- microarray and real time-PCR showed enhanced expression of IL- ceptor for IL-13 in fibrosis-inducing conditions. 13 Ra2 in the dermal compartment in the lesional skin of AD.14 Similarly, IL-13 Ra2deficiency has previously been shown to Serum levels of soluble form IL-13 Ra2 were elevated in AD, lead to increased collagen deposition, and treatment with an IL- and allergic rhinitis, compared with those in non-atopic 13 Ra2 fusion protein has been shown to reduce collagen produc- normal controls.46 In parallel, the immunohistological expression tion.48 In a model of schistosomiasis, IL-13 Ra2 was elevated in of IL-13 Ra2 was markedly enhanced in the lesional epidermis of serum following Schistosoma mansoni infection.49 IL-13 Ra2defi- AD compared with normal skin.42 However, clinical relevance of IL- ciency resulted in decreased survival, increased granuloma size, 13 Ra2 in the disease severity and treatment response remains and increased liver fibrosis,49 again suggesting the protective elusive in AD. Further studies are warranted to elucidate the clinical function of IL-13 Ra2. value of this biomarker in AD. Although most studies have indicated that IL-13 Ra2 is a decoy In an AD-like mouse model induced by repeated topical appli- receptor, one research group showed that IL-13 signals through IL- cation of Aspergillus fumigatus extract, mice lacking IL-13 Ra2 13 Ra2 to induce TGF-b and promote fibrosis (Fig. 2).50 In this exhibited significantly increased transepidermal water loss, cuta- context, recent studies have revealed that IL-13 Ra2 can be acti- neous inflammation, peripheral eosinophilia, and IgG1 and IgE vated by another ligand, chitinase 3-like 1 (CHI3L1), also known as 414 M. Furue et al. / Allergology International 69 (2020) 412e416

Fig. 1. Scratching and IL-13 upregulate IL-13 Ra2 expression. IL-13 produced from Th2 cells and type 2 innate lymphoid cells (ILC2) plays a pivotal pathogenic role in atopic dermatitis. IL-13 binds to its heterodimeric receptor, IL-4Ra and IL-13 Ra1, and aggravates barrier dysfunction by downregulating epidermal terminal differentiation molecules such as filaggrin (FLG) and involucrin (INV). IL-13 also activates the sensory nerve to induce itch sensation and subsequent scratching. A second receptor, IL-13 Ra2, is a decoy receptor that binds to IL-13 with high affinity, internalizes IL-13 and lowers the IL-13 level in the milieu. The expression of IL-13 Ra2 is upregulated by IL-13 and mechanical scratching in keratinocytes. The overexpression of IL-13 Ra2 does inhibit IL-13 signals. Thus, the IL-13 signal is finely tuned by mechanical scratching and by IL-13 itself via IL-13 Ra2 upregulation. breast regression protein 39 (BRP-39) in mice and human homo- TMEM219 axis.52 Further studies are warranted to clarify multi- logue YKL-40.51,52 Serum and cutaneous levels of CHI3L1/YKL-40 faceted biological function of IL-13 Ra2. are increased in patients with AD.51 In murine AD model, CHI3L1/ YKL-40 is involved in Th2 deviation and M2 activa- Conclusion tion.51 Lee et al. have demonstrated that CHI3L1/YKL-40 binds to IL- 52 13 Ra2 and signals via membrane-bound TMEM219 molecule. The major symptom in AD is the persistent and vicious itch- Interestingly, TMEM219 facilitates IL-13 and IL-13 Ra2 binding scratch cycle. The itch-scratch response appears to exacerbate the 52 ability and contributes to the decoy function of IL-13 Ra2. As skin lesion and results in chronic lichenification. It has been re- TMEM219 is involved in TGF-b induction, both CHI3L1/YKL-40 and ported that IL-13 Ra2 is overexpressed both in the epidermal and IL-13 and may induce TGF-b and promote fibrosis via IL-13 Ra2/ dermal compartments in the lesional skin of AD.14,42,44,45 The

Fig. 3. Implication of IL-13 Ra2 in atopic dermatitis. IL-13 and mechanical scratching are potent inducers of IL-13 Ra2 expression. As IL-13 Ra2 works as a decoy receptor for Fig. 2. IL-13 Ra2 may regulate dermal fibrosis. IL-13 is a potent pro-fibrotic cytokine. IL-13, scratching delivers a compensatory response against IL-13-mediated atopic IL-13 and itch/scratch stimulation upregulate the IL-13 Ra2. Due to its decoy function, inflammation via IL-13 Ra2 upregulation. However, another ligand CHI3L1/YKL-40 may the upregulated IL-13 Ra2 may downregulate the IL-13-mediated fibrosis. However, IL- promote the fibrosing process via IL-13 Ra2/TMEM219 axis. We assume that the 13 Ra2 has another ligand called YKL-40 which promotes fibrotic process. These fine- reactive response of upregulated IL-13 Ra2 is not enough to compensate the over- tuned, feed-back or feed-forward regulatory mechanisms operate and finally develop whelming IL-13 effects and that the scratched lesion may eventually form a charac- fibrosis or dermal remodeling in atopic dermatitis. teristic lichenified and fibrotic lesion in atopic dermatitis. M. Furue et al. / Allergology International 69 (2020) 412e416 415 majority of in vitro and in vivo experiments indicated that IL-13 Ra2 19. Ranasinghe C, Trivedi S, Wijesundara DK, Jackson RJ. IL-4 and IL-13 receptors: works as a decoy receptor for IL-13; therefore, its overexpression roles in immunity and powerful vaccine adjuvants. Cytokine Growth Factor Rev 2014;25:437e42. attenuates the IL-13-mediated inflammatory responses. Both IL-13 20. Tsoi LC, Rodriguez E, Degenhardt F, Baurecht H, Wehkamp U, Volks N, et al. and mechanical scratching are potent inducers of IL-13 Ra2 Atopic dermatitis is an IL-13-dominant disease with greater molecular het- e expression. IL-13-induced IL-13 Ra2 expression is also synergisti- erogeneity compared to psoriasis. J Invest Dermatol 2019;139:1480 9. 42 21. Wollenberg A, Howell MD, Guttman-Yassky E, Silverberg JI, Kell C, Ranade K, cally augmented by scratching, thus the upregulated IL-13 Ra2 et al. Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb. expression delivers a compensatory response against IL-13- J Allergy Clin Immunol 2019;143:135e41. mediated atopic inflammation. However, we assume that the 22. Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell reactive response of upregulated IL-13 Ra2 is not enough to 2017;171:217e28. compensate the overwhelming IL-13 effects and that the scratched 23. Mitamura Y, Nunomura S, Nanri Y, Ogawa M, Yoshihara T, Masuoka M, et al. lesion may eventually form a characteristic lichenified eruption. In The IL-13/periostin/IL-24 pathway causes epidermal barrier dysfunction in allergic skin inflammation. Allergy 2018;73:1881e91. addition, another ligand CHI3L1/YKL-40 may also promote the 24. Takei K, Mitoma C, Hashimoto-Hachiya A, Uchi H, Takahara M, Tsuji G, et al. fibrosing process via IL-13 Ra2/TMEM219 axis (Fig. 3). Antioxidant soybean tar Glyteer rescues T-helper-mediated downregulation of filaggrin expression via aryl hydrocarbon receptor. J Dermatol 2015;42: 171e80. Acknowledgements 25. van den Bogaard EH, Bergboer JG, Vonk-Bergers M, van Vlijmen-Willems IM, Hato SV, van der Valk PG, et al. 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