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Transcriptome profiling unveils the role of cholesterol in IL-17A signaling in psoriasis

Varshney, Pallavi, Narasimhan, Aarti, Mittal, Shankila, Malik, Garima, Sardana, Kabir, Saini, Neeru·2016·Scientific Reports
DOI 10.1038/srep19295PMC PMC4726068
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Abstract

Psoriasis is a chronic inflammatory skin disease characterized by altered proliferation and differentiation of keratinocytes as well as infiltration of immune cells. Increased expression of Th17 cells and cytokines secreted by them provides evidence for its central role in the pathogenesis of psoriasis. IL-17A, signature cytokine of Th17 cells was found to be highly differentially expressed in psoriatic lesional skin. However, cellular and molecular mechanism by which IL-17A exerts its function on keratinocyte is incompletely understood. To understand IL-17A mediated signal transduction pathways, gene expression profiling was done and differentially expressed genes were analysed by IPA software. Here, we demonstrate that during IL-17A signaling total cholesterol levels were elevated, which in turn resulted in the suppression of genes of cholesterol and fatty acid biosynthesis. We found that accumulation of cholesterol was essential for IL-17A signaling as reduced total cholesterol levels by methyl β cyclodextrin (MBCD), significantly decreased IL-17A induced secretion of CCL20, IL-8 and S100A7 from the keratinocytes. To our knowledge this study for the first time unveils that high level of intracellular cholesterol plays a crucial role in IL-17A signaling in keratinocytes and may explain the strong association between psoriasis and dyslipidemia.

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  • Cholesterol homeostasis is disrupted in psoriatic lesions, with upregulation of cholesterol synthesis pathways, elevated free cholesterol, and disrupted cellular cholesterol homeostasis.

    “spatial proteomic and biochemical analyses demonstrate significant upregulation of cholesterol synthesis pathways, elevated free cholesterol levels, and disrupted cellular cholesterol homeostasis14–17.”

    From Macrophage INSIG1 deficiency drives psoriasiform dermatitis via the SREBP2-STAT1 axis (2026) · cites this paper as [17]

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Metadata

Authors
Varshney, P., Narasimhan, A., Mittal, S., Malik, G., Sardana, K., & Saini, N.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-01-19
Volume
6
Issue
1
ISSN
2045-2322
DOI
10.1038/srep19295
PMC
PMC4726068
Cited by
64
References
1
Language
en
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