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Essential Role of CARD14 in Murine Experimental Psoriasis

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Essential Role of CARD14 in Murine Experimental Psoriasis Essential Role of CARD14 in Murine Experimental Psoriasis Mayuri Tanaka, Kouji Kobiyama, Tetsuya Honda, Kozue Uchio-Yamada, Yayoi Natsume-Kitatani, Kenji Mizuguchi, This information is current as Kenji Kabashima and Ken J. Ishii of September 28, 2021. J Immunol published online 17 November 2017 http://www.jimmunol.org/content/early/2017/11/17/jimmun ol.1700995 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/11/17/jimmunol.170099 Material 5.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 17, 2017, doi:10.4049/jimmunol.1700995 The Journal of Immunology Essential Role of CARD14 in Murine Experimental Psoriasis Mayuri Tanaka,*,† Kouji Kobiyama,*,†,1 Tetsuya Honda,‡ Kozue Uchio-Yamada,x Yayoi Natsume-Kitatani,{ Kenji Mizuguchi,{ Kenji Kabashima,‡ and Ken J. Ishii*,† Caspase recruitment domain family member 14 (CARD14) was recently identified as a psoriasis-susceptibility gene, but its immunological role in the pathogenesis of psoriasis in vivo remains unclear. In this study, we examined the role of CARD14 in murine experimental models of psoriasis induced by either imiquimod (IMQ) cream or recombinant IL-23 injection. In all models tested, the psoriasiform skin inflammation was abrogated in Card142/2 mice. Comparison of the early gene signature of the skin between IMQ-cream–treated Card142/2 mice and Tlr72/2Tlr92/2 mice revealed not only their similarity, but also distinct gene sets targeted by IL-23. Cell type–specific analysis of these mice identified skin Langerinhigh Langerhans cells as a potent producer of IL-23, which was dependent on both TLR7 and TLR9 but independent of CARD14, suggesting that CARD14 is acting downstream of IL-23, not TLR7 or TLR9. Instead, a bone marrow chimera study suggested that CARD14 in radio-sensitive hematopoietic cells was required for IMQ-induced psoriasiform skin inflammation, controlling the number of Vg4+ T cells Downloaded from producing IL-17 or IL-22 infiltrating through the dermis to the inflamed epidermis. These data indicate that CARD14 is essential and a potential therapeutic target for psoriasis. The Journal of Immunology, 2018, 200: 000–000. soriasis is a chronic inflammatory skin disorder that is signaling pathways mediated by multiple TLRs are critical for the predominantly characterized by sharply demarcated development of psoriasis (5). However, no reports have firmly P chronic erythematous plaques (1). Although its etiological demonstrated the dual requirement of both TLR7 and TLR9 by http://www.jimmunol.org/ mechanisms are largely unknown, recent evidence suggests that using doubly deficient mice for TLR7 and TLR9, for example. the topical application of imiquimod (IMQ) cream causes In addition to innate immune recognition and signaling, in- psoriasis-like skin inflammation in humans and mice (2, 3). Al- flammatory cytokines such as IL-17 and IL-23 hold the key though IMQ is an agonist of mouse TLR7, TLR7-deficient mice to understanding the pathogenesis of psoriasis (6). mAbs against display epidermal hyperplasia comparable to that displayed by IL-23p19 (guselkumab and tildrakizumab) showed more clinical wild type (WT) mice in an IMQ-induced psoriasis model (4), benefit than blockage of the IL-12/23p40 subunit in human pa- suggesting that TLR7-independent mechanisms contribute to this tients (6, 7). In an experimental setting, an absence of IL-23p19 pathogenesis. Indeed, accumulating evidence has suggested that in vivo abrogated IMQ-induced psoriasis-like skin inflammation both TLR7 and TLR9 are involved in the activation of dendritic (2). Vice versa, intradermal injections of mouse ears with by guest on September 28, 2021 cells (DCs) in human psoriasis, indicating that the innate immune recombinant IL-23 protein (rIL-23) also reproduced many features of psoriasis, such as the upregulation of IL-22 and epidermal hyperplasia via the activation of STAT3 (8, 9). Overall, the IMQ- *Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, and IL-23–induced skin inflammation models in mice tightly National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567- 0085, Japan; †Laboratory of Vaccine Science, World Premier International Research linked to IL-17 and IL-22 production are useful animal models for Center Initiative Immunology Frontier Research Center, Osaka University, Osaka psoriasis (8–10). 567-0871, Japan; ‡Department of Dermatology, Kyoto University Graduate School x Despite increasing evidence that IL-23p19 plays a crucial role in of Medicine, Kyoto 606-8507, Japan; Laboratory of Animal Models for Human Diseases, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka autoimmune diseases, the cell types involved and the mechanisms of { 567-0085, Japan; and Laboratory of Bioinformatics, National Institutes of Biomed- IL-23p19 production are not fully understood. Langerin2 conven- ical Innovation, Health and Nutrition, Osaka 567-0085, Japan tional DCs have been shown to be the major sources of IL-23p19 in 1Current address: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA. IMQ-induced psoriasis (11), whereas other reports suggest that + ORCIDs: 0000-0003-3021-7078 (K.M.); 0000-0002-6728-3872 (K.J.I.). Langerin Langerhans cells (LCs) in mice (12) and humans (13) in Received for publication July 24, 2017. Accepted for publication October 19, 2017. psoriasis, as well as epidermal keratinocytes in patients with atopic This work was supported by grants from the Ministry of Education, Culture, Sports, dermatitis (14) or psoriasis (15), are potential sources of IL-23p19. Science and Technology of Japan, the Japan Agency for Medical Research and De- Nevertheless, the secreted IL-23p19 in turn can activate velopment, and the Ministry of Health, Labour, and Welfare Sciences. IL-17– and IL-22–producing gd T cells, critical cell types in the The gene expression microarray data presented in this article have been submitted to pathogenesis of psoriasis (9). IL-23R is highly expressed on gd the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE104603) under accession number GSE104603. T cells, and mutations in IL-23R are associated with psoriasis in Address correspondence and reprint requests to Prof. Ken J. Ishii, Laboratory of humans (9, 16). In murine skin, gd T cells exist abundantly as Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes dendritic epidermal gd T cells (DETCs), which are characterized of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito Asagi, Ibaraki City, Osaka 567- by the expression of the Vg5+ TCR (nomenclature of Heilig and 0085, Japan. E-mail address: [email protected] Tonegawa) and participate in tissue surveillance and wound The online version of this article contains supplemental material. healing (17–19). Vg4+gd T cells are also the main producers of Abbreviations used in this article: BCL10, B cell lymphoma 10; BM, bone marrow; CARD14, caspase recruitment domain family member 14; DC, dendritic cell; DETC, IL-17 in psoriasis models (9, 19). gd T cells are infrequent in dendritic epidermal gd T cells; IMQ, imiquimod; K5, keratin 5; LC, Langerhans cell; human skin compared with the number of DETCs in healthy LN, lymph node; rIL-23, recombinant IL-23; WT, wild type. mouse skin, whereas Vg9Vd2 T cells are reported to be a proin- Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$35.00 flammatory subset in psoriasis patients (20). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700995 2 CARD14 CONTROLS IL-23–MEDIATED gdT17 CELLS Recently, caspase recruitment domain family member 14 experiment (WT, Ly5.1-B6, or Card142/2) received a lethal dose of x-rays (CARD14, also known as CARMA2 or BIMP2), encoded at the (8.5 Gy), then reconstituted with an i.v. injection of BM cells through the psoriasis susceptibility locus 2 located in human chromosomal orbital sinus. Chimerism in the peripheral blood was measured as the percentage of donor cells (.90%) in the chimeric mice at least 10 wk after region 17q25.3, was shown to have unique gain-of-function mu- reconstitution, after which applications of IMQ cream were commenced. tations associated with psoriasis (21). This finding was confirmed in a genome-wide association study of psoriasis susceptibility Histopathology of ear skin locus 2, which identified several risk-associated variants, includ- The mice were sacrificed on the final day of the experiment. Their ears were ing mutations in CARD14 (16). CARD14, like CARD11, is a collected and fixed in 10 N formalin for subsequent embedding in paraffin. novel membrane-associated guanylate kinase family member, Paraffin tissue sections (4 mm thick) were deparaffinized and stained with a which functions as an upstream activator of B cell lymphoma 10 rabbit polyclonal Abs directed against mouse keratin 5 (K5) (1:400; Covance), or a rabbit mAb directed against mouse Ki67 (Thermo Fisher (BCL10) and NF-kB signaling (22). Although CARD11 is pref- Scientific). Before the primary Ab was added, the sections were treated erentially expressed in hematopoietic cells, CARD14 is expressed with 0.01 M citric acid (adjusted to pH 6) for 10 min at 80˚C. The sec- more ubiquitously in certain tissues such as skin (21).
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