A20 and ABIN1 Suppression of a Keratinocyte Inflammatory Program with a Shared Single-Cell Expression Signature in Diverse Human Rashes.
Cells, Cultured
DNA-Binding Proteins
/ immunology
Dermatitis, Atopic
/ immunology
Erythrokeratodermia Variabilis
/ immunology
Exanthema
/ immunology
Genomics
Humans
Interleukin-17
/ immunology
Keratinocytes
/ immunology
Primary Cell Culture
Psoriasis
/ immunology
RNA-Seq
Signal Transduction
/ immunology
Single-Cell Analysis
Skin
/ cytology
Tumor Necrosis Factor alpha-Induced Protein 3
/ immunology
Tumor Necrosis Factor-alpha
/ immunology
Up-Regulation
Journal
The Journal of investigative dermatology
ISSN: 1523-1747
Titre abrégé: J Invest Dermatol
Pays: United States
ID NLM: 0426720
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
01
05
2018
revised:
17
10
2018
accepted:
26
10
2018
pubmed:
14
12
2018
medline:
10
5
2020
entrez:
14
12
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30543901
pii: S0022-202X(18)32924-5
doi: 10.1016/j.jid.2018.10.046
pmc: PMC6642632
mid: NIHMS1522377
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Interleukin-17
0
TNF protein, human
0
TNIP1 protein, human
0
Tumor Necrosis Factor-alpha
0
TNFAIP3 protein, human
EC 3.4.19.12
Tumor Necrosis Factor alpha-Induced Protein 3
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1264-1273Subventions
Organisme : NIAMS NIH HHS
ID : K08 AR067243
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR057216
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR051930
Pays : United States
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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