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Interleukin-17A Drives IL-19 and IL-24 Expression in Skin Stromal Cells Regulating Keratinocyte Proliferation

Authors
  • Xu, Xiaofei1, 2, 3
  • Prens, Errol2
  • Florencia, Edwin1, 2, 3
  • Leenen, Pieter3
  • Boon, Luis4
  • Asmawidjaja, Patrick1, 3
  • Mus, Anne-Marie1, 3
  • Lubberts, Erik1, 3
  • 1 Department of Rheumatology, Erasmus Medical Center, Rotterdam , (Netherlands)
  • 2 Department of Dermatology, Erasmus Medical Center, Rotterdam , (Netherlands)
  • 3 Department of Immunology, Erasmus Medical Center, Rotterdam , (Netherlands)
  • 4 Polypharma Biologics, Utrecht , (Netherlands)
Type
Published Article
Journal
Frontiers in Immunology
Publisher
Frontiers Media SA
Publication Date
Sep 20, 2021
Volume
12
Identifiers
DOI: 10.3389/fimmu.2021.719562
PMID: 34616394
PMCID: PMC8488340
Source
PubMed Central
Keywords
Disciplines
  • Immunology
  • Original Research
License
Unknown

Abstract

IL-17A has been shown to be up-regulated in psoriasis lesions and is central to psoriasis pathogenesis. IL-19, along with other IL-20 subfamily cytokines such as IL-20 and IL-24, is induced by IL-17A and contributes especially to epidermal hyperplasia in psoriasis. However, the regulation, cellular sources of IL-19 and whether targeting of IL-17A by biologics influence IL-19 expression is not completely understood. To investigate the regulation of IL-19 by IL-17A in psoriasis, the imiquimod-induced psoriasis mouse (IMQ) model was used. Enhanced expression of IL-17A in the IMQ model was achieved by anti-IL-10 antibody treatment. Assessments of skin inflammation macroscopically, by histology and flow cytometry, all confirmed increased psoriatic symptoms. Interestingly, depletion of IL-10 markedly upregulated IL-23/IL-17 pathway related cytokines followed by a significant increase in IL-19 and IL-24. The up-regulation of IL-19 and IL-24, but not IL-17A, coincided with increased keratinocyte proliferation. To investigate the cellular source and effects of biologics on IL-19, human skin fibroblasts from healthy controls and psoriasis patients were cultured alone or co-cultured with activated memory CD4+ T cells. Besides IL-1β, IL-17A induced direct expression of IL-19 and IL-24 in skin fibroblasts and keratinocytes. Importantly, intrinsic higher expression of IL-19 in psoriatic skin fibroblasts was observed in comparison to healthy skin fibroblasts. Neutralization of IL-17A in the human skin fibroblast-T cell co-culture system significantly suppressed IL-19 and IL-24 expression. Together, our data show that IL-17A-induced IL-19 and IL-24 expression in skin stromal cells contribute to keratinocyte proliferation.

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