Abstract
Genetic mutations of CARD14 (encoding CARMA2) are observed in psoriasis patients. Here we showed that Card14E138A/+ and Card14ΔQ136/+ mice developed spontaneous psoriasis-like skin inflammation, which resulted from constitutively activated CARMA2 via self-aggregation leading to the enhanced activation of the IL-23-IL-17A cytokine axis. Card14-/- mice displayed attenuated skin inflammation in the imiquimod-induced psoriasis model due to impaired IL-17A signaling in keratinocytes. CARMA2, mainly expressed in keratinocytes, associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-κB and MAPK signaling pathway activation, which leads to expression of pro-inflammatory factors. Thus, CARMA2 serves as a key mediator of IL-17A signaling and its constitutive activation in keratinocytes leads to the onset of psoriasis, which indicates an important role of NF-κB activation in keratinocytes in psoriatic initiation.
Copyright © 2018 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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CARD Signaling Adaptor Proteins / chemistry
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CARD Signaling Adaptor Proteins / deficiency
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CARD Signaling Adaptor Proteins / genetics*
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CARD Signaling Adaptor Proteins / metabolism*
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Cell Line
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Cytokines / genetics
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Cytokines / metabolism
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Dermatitis / genetics*
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Dermatitis / physiopathology
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Gain of Function Mutation*
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Gene Expression Regulation / drug effects
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Guanylate Kinases / chemistry
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Guanylate Kinases / deficiency
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Guanylate Kinases / genetics*
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Guanylate Kinases / metabolism*
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HEK293 Cells
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Humans
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Imiquimod
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Interleukin-17 / metabolism*
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Keratinocytes / metabolism*
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Keratinocytes / pathology
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Psoriasis / chemically induced
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Psoriasis / genetics*
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Psoriasis / physiopathology
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Signal Transduction
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T-Lymphocyte Subsets / metabolism
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TNF Receptor-Associated Factor 6 / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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CARD Signaling Adaptor Proteins
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Cytokines
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Il17a protein, mouse
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Interleukin-17
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NF-kappa B
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TNF Receptor-Associated Factor 6
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Traf3ip2 protein, mouse
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Card14 protein, mouse
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Guanylate Kinases
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Imiquimod