Abstract
Psoriasis is a chronic, inflammatory skin disease caused by a combination of environmental and genetic factors. The Tnip1 gene encodes A20 binding and inhibitor of NF-κB-1 (ABIN-1) protein and is strongly associated with susceptibility to psoriasis in humans. ABIN-1, a widely expressed ubiquitin-binding protein, restricts TNF- and TLR-induced signals. In this study, we report that mice lacking ABIN-1 specifically in dendritic cells (DCs), ABIN-1(fl) CD11c-Cre mice, exhibit perturbed immune homeostasis. ABIN-1-deficient DCs display exaggerated NF-κB and MAPK signaling and produce more IL-23 than do normal cells in response to TLR ligands. Challenge of ABIN-1(fl) CD11c-Cre mice with topical TLR7 ligand leads to greater numbers of Th17 and TCRγδ T cells and exacerbated development of psoriaform lesions. These phenotypes are reversed by DC-specific deletion of the TLR adaptor MyD88. These studies link ABIN-1 with IL-23 and IL-17, and they provide cellular and molecular mechanisms by which ABIN-1 regulates susceptibility to psoriasis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Cells, Cultured
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Dendritic Cells / immunology
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Dendritic Cells / metabolism*
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Disease Susceptibility
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Inflammation
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Interleukin-17 / metabolism*
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Interleukin-23 / metabolism*
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitogen-Activated Protein Kinases / metabolism
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism*
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NF-kappa B / metabolism
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Psoriasis / genetics
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Psoriasis / immunology*
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Psoriasis / metabolism
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Signal Transduction
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Th17 Cells / immunology
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Toll-Like Receptor 7 / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Interleukin-17
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Interleukin-23
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NF-kappa B
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Tlr7 protein, mouse
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Tnip2 protein, mouse
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Toll-Like Receptor 7
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Mitogen-Activated Protein Kinases