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Expanding the psoriasis disease profile: interrogation of the skin and serum of patients with moderate-to-severe psoriasis.

Suárez-Fariñas M, Li K, Fuentes-Duculan J, Hayden K, Brodmerkel C, Krueger JG - J. Invest. Dermatol. (2012)

Bottom Line: This new analysis identified 4,175 probe sets (representing 2,725 unique known genes) as being differentially expressed in psoriasis lesions compared with matched biopsies of non-lesional skin when the following criteria were applied: >2-fold change and false discovery rate <0.05.These probe sets represent the largest and most comprehensive set of genes defining psoriasis at the molecular level and within the previously unidentified genes, a link to functional pathways associated with metabolic diseases/diabetes and to cardiovascular risk pathways is identified.We identified linkage of functional pathways in lesional skin associated with metabolic diseases/diabetes and cardiovascular risk with those pathways overexpressed in the serum, suggesting a potential linkage between altered gene transcription in the skin and comorbidities commonly seen in patients with moderate-to-severe psoriasis.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Investigative Dermatology, Rockefeller University, New York, New York, USA.

ABSTRACT
Psoriasis is a complex disease with an expanding definition of its pathological features. We sought to expand/refine the psoriasis transcriptome using 85 paired lesional and non-lesional samples from a cohort of patients with moderate-to-severe psoriasis vulgaris who were not receiving active psoriasis therapy. This new analysis identified 4,175 probe sets (representing 2,725 unique known genes) as being differentially expressed in psoriasis lesions compared with matched biopsies of non-lesional skin when the following criteria were applied: >2-fold change and false discovery rate <0.05. These probe sets represent the largest and most comprehensive set of genes defining psoriasis at the molecular level and within the previously unidentified genes, a link to functional pathways associated with metabolic diseases/diabetes and to cardiovascular risk pathways is identified. In addition, we profiled the serum of moderate-to-severe psoriatics compared with healthy controls to assess the overlap of overexpressed lesional genes with overexpressed systemic proteins. We identified linkage of functional pathways in lesional skin associated with metabolic diseases/diabetes and cardiovascular risk with those pathways overexpressed in the serum, suggesting a potential linkage between altered gene transcription in the skin and comorbidities commonly seen in patients with moderate-to-severe psoriasis.

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Related in: MedlinePlus

Protein expression of previously unreported genes detected in this transcriptome. Representative immunohistochemistry staining in normal, non-lesional, and lesional psoriasis skin (n=5). (a) Renin was highly expressed by scattered cells in the papillary and upper reticular dermis mostly in lesional skin compared with non-lesional and normal skin. (b) Cytotoxic T-lymphocyte antigen (CTLA4) was expressed on keratinocytes and some dermal cells in lesional skin compared with very little expression on non-lesional skin and none on normal skin. (c) Toll-like receptor (TLR3) was strongly expressed on keratinocytes of lesional skin compared with a faint expression on normal and non-lesional skin. Scale bar=100 μm.
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fig2: Protein expression of previously unreported genes detected in this transcriptome. Representative immunohistochemistry staining in normal, non-lesional, and lesional psoriasis skin (n=5). (a) Renin was highly expressed by scattered cells in the papillary and upper reticular dermis mostly in lesional skin compared with non-lesional and normal skin. (b) Cytotoxic T-lymphocyte antigen (CTLA4) was expressed on keratinocytes and some dermal cells in lesional skin compared with very little expression on non-lesional skin and none on normal skin. (c) Toll-like receptor (TLR3) was strongly expressed on keratinocytes of lesional skin compared with a faint expression on normal and non-lesional skin. Scale bar=100 μm.

Mentions: An IPA of the whole psoriasis transcriptome identified in this study yielded dermatological conditions (379 genes, P<10−70), genetic disorder (361 genes, P<10−74), cancer (968 genes, P<10−64), and gastrointestinal disease (893 genes, P<10−26) as the four top associations, the subcategories of which contain the links to non-insulin-dependent diabetes, coronary artery disease, and inflammatory bowel disease previously discussed. Within the inflammatory, immune response and cardiovascular disorders categories, interesting previously unreported psoriasis genes included cytotoxic T-lymphocyte antigen (CTLA)-4, Toll-like receptor (TLR)-3, and renin. We confirmed via immunohistochemistry that protein products of these genes were expressed at high levels in psoriasis plaques (Figure 2). CTLA4 staining was observed on keratinocytes and dermal cells, whereas TLR3 was expressed mostly on keratinocytes. In contrast, renin was expressed at very high levels by scattered cells in the papillary and upper reticular dermis. Among the canonical pathways collection (Supplementary Figure S1d online), IPA-identified metabolism involved pathways such as artherosclerosis signaling, PPARα activation, RAR activation, renin–angiotensin signaling, and leptin signaling (P<10−2 all cases). The enrichment of PPARα/RAR as well as IL-1-mediated inhibition ofRXR agrees with data presented by Romanowska and colleagues (2010). Additionally, 3 of the top 10 pathways were macrophage-related pathways and included Fcγ receptor–mediated phagocytosis in macrophages and monocytes, and iNOS production in macrophages. Wnt and FGF signaling pathways were not significant in our analysis. IPA also identified transcription factors activated or in our transcriptome. Of relevance, downstream genes regulated by STAT1, 2, and 3 were found to be activated. Interestingly, the transcription factor NROB2 is implicitly activated, and its function of downregulating targeting genes could possibly explain suppressed PPARα and RAR network alterations.


Expanding the psoriasis disease profile: interrogation of the skin and serum of patients with moderate-to-severe psoriasis.

Suárez-Fariñas M, Li K, Fuentes-Duculan J, Hayden K, Brodmerkel C, Krueger JG - J. Invest. Dermatol. (2012)

Protein expression of previously unreported genes detected in this transcriptome. Representative immunohistochemistry staining in normal, non-lesional, and lesional psoriasis skin (n=5). (a) Renin was highly expressed by scattered cells in the papillary and upper reticular dermis mostly in lesional skin compared with non-lesional and normal skin. (b) Cytotoxic T-lymphocyte antigen (CTLA4) was expressed on keratinocytes and some dermal cells in lesional skin compared with very little expression on non-lesional skin and none on normal skin. (c) Toll-like receptor (TLR3) was strongly expressed on keratinocytes of lesional skin compared with a faint expression on normal and non-lesional skin. Scale bar=100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472561&req=5

fig2: Protein expression of previously unreported genes detected in this transcriptome. Representative immunohistochemistry staining in normal, non-lesional, and lesional psoriasis skin (n=5). (a) Renin was highly expressed by scattered cells in the papillary and upper reticular dermis mostly in lesional skin compared with non-lesional and normal skin. (b) Cytotoxic T-lymphocyte antigen (CTLA4) was expressed on keratinocytes and some dermal cells in lesional skin compared with very little expression on non-lesional skin and none on normal skin. (c) Toll-like receptor (TLR3) was strongly expressed on keratinocytes of lesional skin compared with a faint expression on normal and non-lesional skin. Scale bar=100 μm.
Mentions: An IPA of the whole psoriasis transcriptome identified in this study yielded dermatological conditions (379 genes, P<10−70), genetic disorder (361 genes, P<10−74), cancer (968 genes, P<10−64), and gastrointestinal disease (893 genes, P<10−26) as the four top associations, the subcategories of which contain the links to non-insulin-dependent diabetes, coronary artery disease, and inflammatory bowel disease previously discussed. Within the inflammatory, immune response and cardiovascular disorders categories, interesting previously unreported psoriasis genes included cytotoxic T-lymphocyte antigen (CTLA)-4, Toll-like receptor (TLR)-3, and renin. We confirmed via immunohistochemistry that protein products of these genes were expressed at high levels in psoriasis plaques (Figure 2). CTLA4 staining was observed on keratinocytes and dermal cells, whereas TLR3 was expressed mostly on keratinocytes. In contrast, renin was expressed at very high levels by scattered cells in the papillary and upper reticular dermis. Among the canonical pathways collection (Supplementary Figure S1d online), IPA-identified metabolism involved pathways such as artherosclerosis signaling, PPARα activation, RAR activation, renin–angiotensin signaling, and leptin signaling (P<10−2 all cases). The enrichment of PPARα/RAR as well as IL-1-mediated inhibition ofRXR agrees with data presented by Romanowska and colleagues (2010). Additionally, 3 of the top 10 pathways were macrophage-related pathways and included Fcγ receptor–mediated phagocytosis in macrophages and monocytes, and iNOS production in macrophages. Wnt and FGF signaling pathways were not significant in our analysis. IPA also identified transcription factors activated or in our transcriptome. Of relevance, downstream genes regulated by STAT1, 2, and 3 were found to be activated. Interestingly, the transcription factor NROB2 is implicitly activated, and its function of downregulating targeting genes could possibly explain suppressed PPARα and RAR network alterations.

Bottom Line: This new analysis identified 4,175 probe sets (representing 2,725 unique known genes) as being differentially expressed in psoriasis lesions compared with matched biopsies of non-lesional skin when the following criteria were applied: >2-fold change and false discovery rate <0.05.These probe sets represent the largest and most comprehensive set of genes defining psoriasis at the molecular level and within the previously unidentified genes, a link to functional pathways associated with metabolic diseases/diabetes and to cardiovascular risk pathways is identified.We identified linkage of functional pathways in lesional skin associated with metabolic diseases/diabetes and cardiovascular risk with those pathways overexpressed in the serum, suggesting a potential linkage between altered gene transcription in the skin and comorbidities commonly seen in patients with moderate-to-severe psoriasis.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Investigative Dermatology, Rockefeller University, New York, New York, USA.

ABSTRACT
Psoriasis is a complex disease with an expanding definition of its pathological features. We sought to expand/refine the psoriasis transcriptome using 85 paired lesional and non-lesional samples from a cohort of patients with moderate-to-severe psoriasis vulgaris who were not receiving active psoriasis therapy. This new analysis identified 4,175 probe sets (representing 2,725 unique known genes) as being differentially expressed in psoriasis lesions compared with matched biopsies of non-lesional skin when the following criteria were applied: >2-fold change and false discovery rate <0.05. These probe sets represent the largest and most comprehensive set of genes defining psoriasis at the molecular level and within the previously unidentified genes, a link to functional pathways associated with metabolic diseases/diabetes and to cardiovascular risk pathways is identified. In addition, we profiled the serum of moderate-to-severe psoriatics compared with healthy controls to assess the overlap of overexpressed lesional genes with overexpressed systemic proteins. We identified linkage of functional pathways in lesional skin associated with metabolic diseases/diabetes and cardiovascular risk with those pathways overexpressed in the serum, suggesting a potential linkage between altered gene transcription in the skin and comorbidities commonly seen in patients with moderate-to-severe psoriasis.

Show MeSH
Related in: MedlinePlus