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Expression profiles of whole skin samples from keratinocyte-specific TRAF6 deficient mice treated with and without IMQ treatment

ABSTRACT: Tumor necrosis factor receptor associated factor 6 (TRAF6) is an adaptor protein that regulates NF-κB and MAPK signaling pathway and is reported to affect immune response and cell death in immune cells. However, the roles of TRAF6 in epithelium have not been well investigated. Using a mouse model of imiquimod-induced psoriasis dermatitis, we show that TRAF6 in epithelial cells totally regulates IL-17-mediated inflammation in the skin. Mice lacking TRAF6 in keratinocytes were unable to activate dendritic cells and failed to produce IL-23 or initiate IL-17 production from γδ T cells at the imiquimod-treated sites. Subcutaneous administrations of IL-23 restored IL-17 production in the mutant animals, suggesting that the induction of IL-23 production is the major TRAF6-dependent contribution of keratinocytes to this process. Therefore, the epithelial TRAF6 signaling is supposed to play an essential role in instructing and propagating the cutaneous immune response. To broadly characterize the impact of the lack of TRAF6 in keratinocytes on the skin inflammation, we analyzed gene expression in IMQ-treated whole ears of Traf6EKO mice and Traf6f/f mice using a cDNA microarray.

ORGANISM(S): Mus musculus

PROVIDER: GSE101077 | GEO | 2018/10/16

REPOSITORIES: GEO

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Project description:The success of TNF inhibitors for treatment of psoriasis and other inflammatory diseases was previously attributed to blockade of innate immunity. In a clinical trial using etanercept TNF blocking agent to treat psoriasis vulgaris, we used affymetrix gene arrays to analyze broad gene profiles in lesional skin at multiple timepoints during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. This analysis created a temporal model of TNF-dependent gene regulation that informs molecular mechanisms of TNF-mediated inflammation. We identified four gene clusters that were differentially down-modulated during etanercept treatment: the cluster down-regulated most rapidly contained mostly dendritic cell activation genes. Culturing human keratinocytes with TNF, IFNg and IL-17 generated a list of keratinocyte genes regulated by each cytokine. The IL-17 pathway genes were strongly down-modulated early, whereas IFNg pathway genes were not down-modulated until final disease resolution at week 12. Finally, we show that TNF blockade rapidly inhibits IL-12/IL-23 p40 subunit expression, and that p40 neutralization inhibits psoriatic dermal emigre-mediated Th17 polarization. We hypothesize that etanercept inhibits myeloid dendritic cell production of IL-23, a Th17 survival cytokine, resulting in rapid downregulation of IL-17 pathway genes. This data links effects of TNF blockade on the innate immune system with the adaptive immune system. Experiment Overall Design: In this study 15 patients with moderate-to-severe psoriasis were given 50mg of etanercept (Amgen) biweekly for 12 weeks. And analyzed using gene array on mRNA extracted from tissue collected at each biopsy time point (non-lesional Time: 0; lesional Time: 0, weeks 1, 2, 4, and 12). Patients were stratified as 'responders' or 'non-responders' based on whether or not they achieved histologic disease resolution by week 12 of etanercept treatment (decreased epidermal thickening, normalization of proliferation marker Ki67, and loss of differentiation marker K16).

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Expression profiles of whole skin samples from keratinocyte-specific TRAF6 deficient mice treated with and without IMQ treatment

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