Dysbiosis-activated IL-17-producing T cells promote skin immunopathological progression in mice deficient of the Notch ligand Jag1 in keratinocytes.

Autor: Song EH; The Molecular, Cellular, and Integrative Biosciences (MCIBS) Graduate Program, The Pennsylvania State University, PA, USA; Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center San Antonio, TX, USA., Garcia J Jr; Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center San Antonio, TX, USA., Xiong N; Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center San Antonio, TX, USA; Department of Medicine-Division of Dermatology and Cutaneous Surgery, University of Texas Health Science Center San Antonio, TX , USA. Electronic address: xiongn@uthscsa.edu.
Jazyk: angličtina
Zdroj: Journal of dermatological science [J Dermatol Sci] 2024 Oct; Vol. 116 (1), pp. 14-23. Date of Electronic Publication: 2024 Sep 06.
DOI: 10.1016/j.jdermsci.2024.09.001
Abstrakt: Background: The Notch signaling pathway is an evolutionarily conserved regulatory cascade critical in skin development and homeostasis. Mice deficient of Notch signaling molecules have impaired skin and hair follicle development associated with local tissue inflammation. However, mechanisms underlying skin inflammation and pathology resulting from defective Notch signals are not well understood.
Objective: To dissect molecular and cellular mechanisms underlying development of skin immunopathology in mice defective of the Notch ligand Jagged-1 (Jag1).
Methods: We assessed involvement of microbiota and immune cell subsets in skin pathogenic symptoms in Foxn1 Cre Jag1 fl/fl mice that were deficient of Jag1 in keratinocytes. We also used RNA-seq and 16S rRNA gene-seq analyses to identify molecular factors and bacterial species contributing to skin pathologic symptoms in Foxn1 Cre Jag1 fl/fl mice.
Results: Compared to Jag1-sufficient littermate control mice, Foxn1 Cre Jag1 fl/fl mice had specific expansion of IL-17a-producing T cells accompanying follicular and epidermal hyperkeratosis and cyst formation while antibody blockage of IL-17a reduced the skin pathology. RNA-sequencing and 16S rRNA gene-sequencing analyses revealed dysregulated immune responses and altered microbiota compositions in the skin of Foxn1 Cre Jag1 fl/fl mice. Antibiotic treatment completely prevented over-activation of IL-17a-producing T cells and alleviated skin pathology in Foxn1 Cre Jag1 fl/fl mice.
Conclusion: Dysbiosis-induced over-activation of IL-17a-producing T cells is critically involved in development of skin pathology in Foxn1 Cre Jag1 fl/fl mice, establishing Foxn1 Cre Jag1 fl/fl mice as a useful model to study pathogenesis and therapeutic targets in microbiota-IL-17-mediated skin inflammatory diseases such as hidradenitis suppurativa (HS) and psoriasis.
(Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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