Researchers; Johann E Gudjonsson, Jun Ding, Xing Li, Rajan P Nair, Trilokraj Tejasvi, Zhaohui S Qin, Debashis Ghosh, Abhishek Aphale, Deborah L Gumucio, John J Voorhees, Goncalo R Abecasis and James T Elder - J Invest Dermatol 129: 2795-2804; advance online publication, July 2, 2009; doi:10.1038/jid.2009.173
Correspondence: Dr Johann E Gudjonsson, Department of Dermatology, University of Michigan, 1910 Taubman Center, Ann Arbor, Michigan 48109, USA.
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Psoriasis is a genetically determined inflammatory skin disease. Although the transition from uninvolved into lesional skin is accompanied by changes in the expression of multiple genes, much less is known about the difference between uninvolved skin from psoriatic patients as opposed to skin from normal individuals.
Multiple biochemical and morphological changes were reported decades ago in uninvolved psoriatic skin but remain poorly understood. Here, we show dysregulation of 223 transcripts representing 179 unique genes in uninvolved psoriatic skin, 178 of which were not previously known to be altered in their expression.
The proteins encoded by these transcripts are involved in lipid metabolism, antimicrobial defenses, epidermal differentiation, and control of cutaneous vasculature.
Cluster analysis of transcripts with significantly altered expression identified a group of genes involved in lipid metabolism with highly correlated gene expression.
Promoter analysis showed enrichment for binding sites of three transcription factors; peroxisome proliferator-activator receptor alpha (PPARA), sterol regulatory element-binding protein (SREBF), and estrogen receptor 2 (ESR2), suggesting that the coordinate regulation of lipid metabolic genes may be related to the action of these factors.
Taken together, our results identify a “pre-psoriatic” gene expression signature, suggesting decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin.
INTRODUCTION
Psoriasis is a chronic inflammatory and hyperproliferative skin disease, affecting over 6 million Americans (about 2%) at an estimated cost of $1.6 to 3.2 billion annually (Sander et al., 1993). The disease tends to strike early in life, as the majority of cases are diagnosed in individuals less than 30 years of age, and a significant proportion of these cases are in individuals less than 10 years old (Krueger et al., 1984). Along with the unsightly cutaneous manifestations with a negative impact on the quality of life (Gupta et al., 1993), psoriasis is accompanied by inflammatory arthritis affecting up to 40% of patients (Gladman, 1994).
That psoriasis has a genetic basis is undisputed, but many of the causative genes remain to be identified (Gudjonsson and Elder, 2007). Psoriasis is characterized by complex alterations in epidermal growth and differentiation, along with multiple biochemical, immunological, inflammatory, and vascular abnormalities. It has been firmly established that psoriasis is a T-cell-mediated disease (Nickoloff and Wrone-Smith, 1999; Conrad et al., 2007) and available data suggest that it may have an autoimmune basis (Gudjonsson et al., 2004). Intraepidermal T cells are crucial for the development of psoriatic epidermal hyperplasia (Conrad et al., 2007), and it has been postulated that these cells may be reacting against self-antigens presented by HLA-Cw6 (Johnston et al., 2004), which was recently shown to be the major genetic determinant of psoriasis susceptibility (Nair et al., 2006, 2008).
Lesional psoriatic (PP) skin has been shown to have a pattern of gene expression that is dramatically different from that of normal (NN) skin of unaffected individuals. Some of the earliest genes identified as having distinctive overexpression in PP skin include transforming growth factor-α (Elder et al., 1989), tumor necrosis factor-α (Nickoloff et al., 1991), vascular endothelial growth factor and its receptors (Detmar et al., 1994), proteinase inhibitors such as peptidase inhibitor 3 (SKALP) (Nonomura et al., 1994), hyperproliferation-associated keratins, K16 and K17 (Leigh et al., 1995), and multiple genes mapping to the epidermal differentiation complex on chromosome 1q21, including S100A, loricrin, involucrin, small proline-rich region (SPRR), and late cornified envelope (LCE) genes (Zhao and Elder, 1997). Subsequently, microarray studies have been used to characterize large-scale gene expression changes in PP skin compared with uninvolved, normal-appearing skin from psoriatic patients (PN skin) and/or NN skin (Bowcock et al., 2001; Zhou et al., 2003; Kulski et al., 2005; Romanowska et al., 2008), or to the involved skin of atopic dermatitis patients (de Jongh et al., 2005;Romanowska et al., 2008). These microarray studies have identified many of the candidates suggested in the original candidate gene studies, as well as genes, which, to our knowledge, are previously unreported/unknown to be implicated in the pathogenesis of psoriasis. However, until now, detailed comparisons of PNversus NN skin involving large numbers of patients have been lacking.
Psoriatic skin has been shown to have biochemical differences when compared with NN skin, with many of these studies performed over three decades ago (Braun-Falco, 1971; Wilkinson, 1971). Interestingly, these morphologic and metabolic alterations in uninvolved skin include processes of lipid metabolism, predominantly in the horny layer of the skin. These were characterized by changes in phospholipid composition and levels and distribution of several hydrolytic enzymes and dehydrogenases (Braun-Falco, 1971; Wilkinson, 1971). Furthermore, increased biosynthesis of arachidonic acid metabolites (Ziboh et al., 1984) and increased blood flow have been noted in PN skin (Klemp and Staberg, 1983), but the etiology of these changes is unknown.
The purpose of this study was to carefully characterize and compare gene expression in normal (NN) versus unaffected skin (PN) from psoriatic patients. Taking advantage of the large size of our sample, we initially focused on progressive differences between NN versus PN versus PP skin in an effort to gain further insight into the disease process. During our analysis, we identified strong patterns of coordinate expression of genes involved in lipid metabolism as well as innate immunity and keratinocyte differentiation in PN versus NN skin. Taking a bioinformatic approach, we identified three transcription factors that could be responsible for the coordinate expression of these lipid biosynthetic genes.
