دورية أكاديمية
Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma.
| العنوان: | Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma. |
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| المؤلفون: | Gluud M; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Pallesen EMH; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Buus TB; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Gjerdrum LMR; Department of Pathology, Zealand University Hospital, Roskilde, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Lindahl LM; Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark., Kamstrup MR; Department of Dermatology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark., Bzorek M; Department of Pathology, Zealand University Hospital, Roskilde, Denmark., Danielsen M; Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark., Bech R; Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark., Monteiro MN; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Blümel E; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Willerslev-Olsen A; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Lykkebo-Valløe A; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Vadivel CK; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Krejsgaard T; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Bonefeld CM; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Geisler C; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Becker JC; Translational Skin Cancer Research, German Cancer Consortium (DKTK), University Medicine Essen, Essen, and Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany., Koralov SB; Department of Pathology, New York University School of Medicine, New York, NY., Iversen L; Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark., Litman T; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Woetmann A; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Ødum N; LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. |
| المصدر: | Blood [Blood] 2023 Jan 12; Vol. 141 (2), pp. 180-193. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Lymphoma, T-Cell, Cutaneous*/pathology , Skin Diseases*/pathology , Skin Neoplasms*/pathology, Humans ; Filaggrin Proteins ; Quality of Life ; T-Lymphocytes/pathology ; Cytokines/metabolism |
| مستخلص: | Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA-mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier. (© 2023 by The American Society of Hematology.) |
| التعليقات: | Comment in: Blood. 2023 Jan 12;141(2):127-128. (PMID: 36633885) |
| المشرفين على المادة: | 0 (Filaggrin Proteins) 0 (Cytokines) |
| تواريخ الأحداث: | Date Created: 20220919 Date Completed: 20230116 Latest Revision: 20230223 |
| رمز التحديث: | 20240829 |
| DOI: | 10.1182/blood.2022016690 |
| PMID: | 36122387 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood.2022016690 |