A20 and ABIN1 Suppression of a Keratinocyte Inflammatory Program with a Shared Single-Cell Expression Signature in Diverse Human Rashes

Paymann Harirchian, Jerry Lee, Stephanie Hilz, Andrew J. Sedgewick, Bethany E. Perez White, Michael J. Kesling, Thaddeus Mully, Justin Golovato, Matthew Gray, Theodora M. Mauro, Elizabeth Purdom, Esther A. Kim, Hani Sbitany, Tina Bhutani, Charles J. Vaske, Stephen C. Benz, Raymond J. Cho, Jeffrey B. Cheng*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Genetic variation in the NF-κB inhibitors, ABIN1 and A20, increase risk for psoriasis. While critical for hematopoietic immune cell function, these genes are believed to additionally inhibit psoriasis by dampening inflammatory signaling in keratinocytes. We dissected ABIN1 and A20's regulatory role in human keratinocyte inflammation using an RNA sequencing–based comparative genomic approach. Here we show subsets of the IL-17 and tumor necrosis factor–α signaling pathways are robustly restricted by A20 overexpression. In contrast, ABIN1 overexpression inhibits these genes more modestly for IL-17, and weakly for tumor necrosis factor–α. Our genome-scale analysis also indicates that inflammatory program suppression appears to be the major transcriptional influence of A20/ABIN1 overexpression, without obvious influence on keratinocyte viability genes. Our findings thus enable dissection of the differing anti-inflammatory mechanisms of two distinct psoriasis modifiers, which may be directly exploited for therapeutic purposes. Importantly, we report that IL-17–induced targets of A20 show similar aberrant epidermal layer-specific transcriptional upregulation in keratinocytes from diseases as diverse as psoriasis, atopic dermatitis, and erythrokeratodermia variabilis, suggesting a contributory role for epidermal inflammation in a broad spectrum of rashes.

Original languageEnglish (US)
Pages (from-to)1264-1273
Number of pages10
JournalJournal of Investigative Dermatology
Volume139
Issue number6
DOIs
StatePublished - Jun 2019

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Harirchian, P., Lee, J., Hilz, S., Sedgewick, A. J., Perez White, B. E., Kesling, M. J., Mully, T., Golovato, J., Gray, M., Mauro, T. M., Purdom, E., Kim, E. A., Sbitany, H., Bhutani, T., Vaske, C. J., Benz, S. C., Cho, R. J., & Cheng, J. B. (2019). A20 and ABIN1 Suppression of a Keratinocyte Inflammatory Program with a Shared Single-Cell Expression Signature in Diverse Human Rashes. Journal of Investigative Dermatology, 139(6), 1264-1273. https://doi.org/10.1016/j.jid.2018.10.046