Psoriasis and Systemic Inflammatory Diseases: Potential Mechanistic Links between Skin Disease and Co-Morbid Conditions , for Psoriasis Education and Learning Syllabus (PEARLS)

  • Davidovici B
  • Sattar N
  • Jö Rg P
 et al. 
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Psoriasis is now classified as an immune-mediated inflammatory disease (IMID) of the skin. It is being recognized that patients with various IMIDs, including psoriasis, are at higher risk of developing ''systemic'' co-morbidities, e.g., cardiovascular disease (CVD), metabolic syndrome, and overt diabetes. In non-psoriatic individuals, the pathophysiology of obesity, aberrant adipocyte metabolism, diabetes, and CVDs involves immune-mediated or inflammatory path-ways. IMIDs may impact these co-morbid conditions through shared genetic risks, common environmental factors, or common inflammatory pathways that are co-expressed in IMIDs and target organs. Given that pathogenic immune pathways in psoriasis are now well worked out and a large number of inflammatory mediators have been identified in skin lesions, in this review we will consider possible mechanistic links between skin inflammation and increased risks of (1) obesity or metabolic alterations and (2) CVD. In particular, we will discuss how well-established risk factors for CVD can originate from inflammation in other tissues. INTRODUCTION Psoriasis vulgaris is a prototypical Th-1, Th-17, and Th-22 inflammatory disease. It is characterized by expansion and activation of Th-1, Th-17, and Th-22 T cells, with production of associated cytokines such as interferon-g, tumor necrosis factor (TNF), IL-17, and IL-22 in the skin (Lowes et al., 2008; Nograles et al., 2009). In turn, T-cell activation is likely to be controlled by an extensive array of dendritic antigen-presenting cells that are also increased in the skin. Myeloid dendritic cells in psoriasis produce high levels of IL-23 and they strongly stimulate T-cell proliferation in vitro. One type of dendritic cell in psoriasis, the TNF-a/inducible nitric oxide synthase (i-NOS)-producing dendritic cells, produces high levels of TNF, IL-20, and other inflammatory molecules (Lowes et al., 2007). As such, this cell could be a key driver of ''innate'' inflammation, inducing a much wider range of inflammatory molecules in keratinocytes (KCs) or other cell types through TNF-and IL-20-driven pathways. Hence, excess production of IL-1, IL-6, IL-8, vascular endothelial growth factor (VEGF), and numerous chemokines may originate from this pathway. The range of inflammatory molecules produced in psoriasis lesions is also strongly regulated by Th1 and Th17 T cells, as interferon-g, IL-17, and IL-22 each induce a characteristic array of inflammatory products in KCs and other cell types present in psoriasis skin lesions (Nograles et al., 2008). Overall, a vast range of inflammatory products (hundreds of individual gene products as identified on gene arrays) are produced in psoriasis skin lesions and many of these appear to be released into the systemic circulation as a function of severity and extent of skin lesions (Liu et al., 2007). Furthermore, effective treatment of psoriasis reduces the levels of circulating cytokines such as TNF and IL-1, which, at higher sustained levels, are likely risk factors for cardiovascular disease (CVD) (Zaba et al., 2007). A central theme in CVD relates to inflammation as a risk factor for progressive development of atheroma and other vascular alterations. Fisman et al. (2003) put forward the concept of good, bad, and indifferent interleukins for cardiovascular risk, with the recognition that CVD has been linked to increased expression of specific interleukins by epidemiological and/or experimental studies. Figure 1 presents a modification of the Fisman model that has been updated to include a broader classification of inflammation-associated molecules that affect the cardiovascular risk, including cytokines that are not named as interleukins and

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  • Batya B Davidovici

  • Naveed Sattar

  • Prinz C Jö Rg

  • Luis Puig

  • Paul Emery

  • Jonathan N Barker

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