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A20 and ABIN1 Suppression of a Keratinocyte Inflammatory Program with a Shared Single-Cell Expression Signature in Diverse Human Rashes.
- Source :
-
The Journal of investigative dermatology [J Invest Dermatol] 2019 Jun; Vol. 139 (6), pp. 1264-1273. Date of Electronic Publication: 2018 Dec 10. - Publication Year :
- 2019
-
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.<br /> (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Cells, Cultured
DNA-Binding Proteins immunology
Dermatitis, Atopic immunology
Dermatitis, Atopic pathology
Erythrokeratodermia Variabilis immunology
Erythrokeratodermia Variabilis pathology
Exanthema pathology
Genomics
Humans
Interleukin-17 immunology
Interleukin-17 metabolism
Keratinocytes pathology
Primary Cell Culture
Psoriasis immunology
Psoriasis pathology
RNA-Seq
Single-Cell Analysis
Skin cytology
Skin immunology
Skin pathology
Tumor Necrosis Factor alpha-Induced Protein 3 immunology
Tumor Necrosis Factor-alpha immunology
Tumor Necrosis Factor-alpha metabolism
Up-Regulation
DNA-Binding Proteins metabolism
Exanthema immunology
Keratinocytes immunology
Signal Transduction immunology
Tumor Necrosis Factor alpha-Induced Protein 3 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1523-1747
- Volume :
- 139
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of investigative dermatology
- Publication Type :
- Academic Journal
- Accession number :
- 30543901
- Full Text :
- https://doi.org/10.1016/j.jid.2018.10.046